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  • 1.
    Abacan, MaryAnn
    et al.
    Univ Philippines Manila, Inst Human Genet, NIH, Manila, Philippines.
    Alsubaie, Lamia
    KASCH, King Abdulaziz Med City, Riyadh, Saudi Arabia.
    Barlow-Stewart, Kristine
    Univ Sydney, Fac Med & Hlth, Northern Clin Sch, Sydney, NSW, Australia.
    Caanen, Beppy
    Maastricht Univ, Dept Clin Genet, Med Ctr, Maastricht, Netherlands.
    Cordier, Christophe
    SYNLAB Genet, Dept Genet, Lausanne, Switzerland.
    Courtney, Eliza
    Natl Canc Ctr, Div Med Oncol, Canc Genet Serv, Singapore, Singapore.
    Davoine, Emeline
    Lausanne Univ Hosp CHUV, Lausanne, Switzerland.
    Edwards, Janice
    Univ South Carolina, Genet Counseling Program, Transnat Alliance Genet Counseling, Columbia, SC USA.
    Elackatt, Niby J.
    Cloudnine Hosp, Org Rare Dis India, Bangalore, Karnataka, India.
    Gardiner, Kate
    LifeLabs Genet, Toronto, ON, Canada.
    Guan, Yue
    Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA USA.
    Huang, Lian-Hua
    China Med Univ, Sch Nursing, Taichung, Taiwan;Natl Taiwan Univ, Coll Med, Sch Nursing, Taipei, Taiwan.
    Ingvoldstad, Charlotta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Livsstil och rehabilitering vid långvarig sjukdom. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa. Karolinska Univ Hosp, Ctr Fetal Med & Clin Genet, Stockholm, Sweden;Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.
    Kejriwal, Sahil
    Univ Washington, Inst Publ Hlth Genet, Seattle, WA USA.
    Kim, Hyon J.
    Ajou Univ, Med Sch, Suwon, South Korea;Konyang Univ, Grad Sch, Suwon, South Korea.
    Lambert, Deborah
    Natl Rare Dis Off, Dublin, Ireland.
    Lantigua-Cruz, Paulina Araceli
    Univ Med Sci Havana, Havana, Cuba.
    Lee, Juliana M. H.
    Natl Univ Malaysia, Kuala Lumpur, Malaysia.
    Lodahl, Marianne
    Copenhagen Univ Hosp, Rigshosp, Dept Clin Genet, Copenhagen, Denmark.
    Lunde, Ashild
    Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway.
    Macaulay, Shelley
    Univ Witwatersrand, Fac Hlth Sci, Div Human Genet, Johannesburg, South Africa;Natl Hlth Lab Serv, Johannesburg, South Africa.
    Macciocca, Ivan
    Victorian Clin Genet Serv, Melbourne, Vic, Australia.
    Margarit, Sonia
    Clin Alemana Univ Desarrollo, Fac Med, Ctr Genet & Genom, Santiago, Chile.
    Middleton, Anna
    Soc & Eth Res Connecting Sci, Wellcome Genome Campus, Cambridge, England;Univ Cambridge, Fac Educ, Cambridge, England.
    Moldovan, Ramona
    Babes Bolyai Univ, Dept Psychol, Cluj Napoca, Romania.
    Ngeow, Joanne
    Natl Canc Ctr, Div Med Oncol, Canc Genet Serv, Singapore, Singapore.
    Obregon-Tito, Alexandra J.
    Univ Arkansas Med Sci, Little Rock, AR 72205 USA.
    Ormond, Kelly E.
    Stanford Univ, Sch Med, Dept Genet, Stanford, CA USA;Stanford Univ, Sch Med, Stanford Ctr Biomed Eth, Stanford, CA USA;Stanford Univ, Sch Med, 300 Pasteur Dr,MC 5208, Stanford, CA USA.
    Paneque, Milena
    Univ Porto, CGPP Ctr Predict & Prevent Genet, I3S, Porto, Portugal;Univ Porto, IBMC Inst Mol & Cell Biol, Porto, Portugal.
    Powell, Karen
    Cone Hlth Canc Ctr, Greensboro, NC USA.
    Sanghavi, Kunal
    Jackson Lab Genom Med, Farmington, CT USA.
    Scotcher, Diana
    Manchester Univ Hosp NHS Fdn Trust, St Marys Hosp, Manchester Ctr Genom Med, Manchester, Lancs, England.
    Scott, Jenna
    Univ British Columbia, Vancouver, BC, Canada.
    Juhe, Clara Serra
    Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Inst Hosp Mar Invest Med, Ctr Invest Biomed Red Enfermedades Raras, Barcelona, Spain.
    Shkedi-Rafid, Shiri
    Hadassah Hebrew Univ, Med Ctr, Jerusalem, Israel.
    Wessels, Tina-Marie
    Univ Cape Town, Div Human Genet, Cape Town, South Africa.
    Yoon, Sook-Yee
    Natl Univ Malaysia, Kuala Lumpur, Malaysia;Canc Res, Subang Jaya, Malaysia;Univ Malaya, Med Ctr, Kuala Lumpur, Malaysia.
    Wicklund, Catherine
    Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA.
    The Global State of the Genetic Counseling Profession2019Ingår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, nr 2, s. 183-197Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The profession of genetic counseling (also called genetic counselling in many countries) began nearly 50 years ago in the United States, and has grown internationally in the past 30 years. While there have been many papers describing the profession of genetic counseling in individual countries or regions, data remains incomplete and has been published in diverse journals with limited access. As a result of the 2016 Transnational Alliance of Genetic Counseling (TAGC) conference in Barcelona, Spain, and the 2017 World Congress of Genetic Counselling in the UK, we endeavor to describe as fully as possible the global state of genetic counseling as a profession. We estimate that in 2018 there are nearly 7000 genetic counselors with the profession established or developing in no less than 28 countries.

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  • 2.
    Abelson, Anna-Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Genetic Risk Factors for Systemic Lupus Erythematosus: From Candidate Genes to Functional Variants2008Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The aim of this thesis has been to identify genetic variants that increase the susceptibility for Systemic Lupus Erythematosus (SLE), an autoimmune disease caused by a complex interplay between various genetic and environmental factors.

    Five different candidate genes were selected through different strategies, and were analysed for association with SLE in an attempt to distinguish some of the underlying mechanisms of this disease. Two of these genes, PD-L1 and PD-L2, appeared not to contain any major risk factors for SLE in the analysed European and Latin American populations. In two other genes, CD24 and STAT4, there appeared to be population-specific effects. The A57V amino acid substitution in the CD24 gene, previously implicated with multiple sclerosis, was associated in a Spanish cohort, with a weak trend in German samples, and no association in Swedish. The previously reported and highly convincing association of the STAT4 transcription factor gene was confirmed in all our cohorts. Interestingly, the results indicate the presence of at least two independent risk variants: the first, represented by a previously reported SNP, was the strongest in individuals of Northern European ancestry, and the second was more pronounced in individuals from Southern Europe and Latin America. We also report the identification of a novel susceptibility gene. The BANK1 gene, encoding a scaffold protein involved in B-cell activation, contains functional variants affecting important domains, which are associated in all investigated cohorts from Europe and Latin America.

    These results confirm the existence of replicable associations between genetic variants and SLE, which are common and present in many populations. The results also illustrate a certain degree of heterogeneity, where some risk factors could have variable effect in different populations.

    Delarbeten
    1. No evidence of association between genetic variants of the PDCD1 ligands and SLE
    Öppna denna publikation i ny flik eller fönster >>No evidence of association between genetic variants of the PDCD1 ligands and SLE
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    2007 (Engelska)Ingår i: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 8, nr 1, s. 69-74Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    PDCD1, an immunoreceptor involved in peripheral tolerance has previously been shown to be genetically associated with systemic lupus erythematosus (SLE). PDCD1 has two ligands whose genes are located in close proximity on chromosome 9p24. Our attention was drawn to these ligands after finding suggestive linkage to a marker (gata62f03, Z=2.27) located close to their genes in a genome scan of Icelandic families multiplex for SLE. Here, we analyse Swedish trios (N=149) for 23 single nucleotide polymorphisms (SNPs) within the genes of the PDCD1 ligands. Initially, indication of association to eight SNPs was observed, and these SNPs were therefore also analysed in Mexican trios (N=90), as well as independent sets of patients and controls from Sweden (152 patients, 448 controls) and Argentina (288 patients, 288 controls). We do not find support for genetic association to SLE. This is the first genetic study of SLE and the PDCD1 ligands and the lack of association in several cohorts implies that these genes are not major risk factors for SLE.

    Nyckelord
    systemic lupus erythematosus, genetic association, linkage disequilibrium, autoimmunity, PD-L1, PD-L2
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-97760 (URN)10.1038/sj.gene.6364360 (DOI)000243783500009 ()17136123 (PubMedID)
    Tillgänglig från: 2008-11-14 Skapad: 2008-11-14 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    2. Association of a CD24 Gene Polymorphism with Susceptibility to Systemic Lupus Erythematosus
    Öppna denna publikation i ny flik eller fönster >>Association of a CD24 Gene Polymorphism with Susceptibility to Systemic Lupus Erythematosus
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    2007 (Engelska)Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 56, nr 9, s. 3080-3086Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Objective. To determine the potential role of the CD24 A57V gene polymorphism in systemic lupus erythematosus (SLE).

    Methods. We studied 3 cohorts of Caucasian patients and controls. The Spanish cohort included 696 SLE patients and 539 controls, the German cohort included 257 SLE patients and 317 controls, and the Swedish cohort included 310 SLE patients and 247 controls. The CD24 A57V polymorphism was genotyped by polymerase chain reaction, using a predeveloped TaqMan allele discrimination assay. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.

    Results. In the Spanish cohort there was a statistically significant difference in the distribution of the CD24 V allele between SLE patients and controls (OR 3.6 [95% CI 2.13-6.16], P < 0.0001). In addition, frequency of the CD24 V/V genotype was increased in SLE patients compared with controls (OR 3.7 [95% CI 2.16-6.34], P < 0.00001). We sought to replicate this association with SLE in a German population and a Swedish population. A similar trend was found in the German group. The CD24 V/V genotype and the CD24 V allele were more frequent in SLE patients than in controls, although this difference was not statistically significant. No differences were observed in the Swedish group. A meta-analysis of the Spanish and German cohorts demonstrated that the CD24 V allele has a risk effect in SLE patients (pooled OR 1.25 [95% Cl 1.08-1.46], P = 0.003). In addition, homozygosity for the CD24 V risk allele significantly increased the effect (pooled OR 2.1,9 [95% Cl 1.50-3.22], P = 0.00007).

    Conclusion. These findings suggest that the CD24 A57V polymorphism plays a role in susceptibility to SLE in a Spanish population.

    Nyckelord
    Antigens; CD24/*genetics, Cohort Studies, Female, Genetic Predisposition to Disease, Humans, Lupus Erythematosus; Systemic/*genetics, Male, Polymorphism; Genetic
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-97761 (URN)10.1002/art.22871 (DOI)000249832600030 ()17763438 (PubMedID)
    Tillgänglig från: 2008-11-14 Skapad: 2008-11-14 Senast uppdaterad: 2022-01-28Bibliografiskt granskad
    3. Functional Variants in the B-Cell Gene BANK1 are Associated with Systemic Lupus Erythematosus
    Öppna denna publikation i ny flik eller fönster >>Functional Variants in the B-Cell Gene BANK1 are Associated with Systemic Lupus Erythematosus
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    2008 (Engelska)Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 40, nr 2, s. 211-216Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by production of autoantibodies and complex genetic inheritance(1-3). In a genome-wide scan using 85,042 SNPs, we identified an association between SLE and a nonsynonymous substitution (rs10516487, R61H) in the B-cell scaffold protein with ankyrin repeats gene, BANK1. We replicated the association in four independent case-control sets (combined P = 3.7 x 10(-10); OR = 1.38). We analyzed BANK1 cDNA and found two isoforms, one full-length and the other alternatively spliced and lacking exon 2 (Delta 2), encoding a protein without a putative IP3R-binding domain. The transcripts were differentially expressed depending on a branch point-site SNP, rs17266594, in strong linkage disequilibrium (LD) with rs10516487. A third associated variant was found in the ankyrin domain (rs3733197, A383T). Our findings implicate BANK1 as a susceptibility gene for SLE, with variants affecting regulatory sites and key functional domains. The disease-associated variants could contribute to sustained B cell-receptor signaling and B-cell hyperactivity characteristic of this disease.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-97762 (URN)10.1038/ng.79 (DOI)000252732900020 ()
    Tillgänglig från: 2008-11-14 Skapad: 2008-11-14 Senast uppdaterad: 2022-01-28Bibliografiskt granskad
    4. STAT4 Associates with SLE through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk
    Öppna denna publikation i ny flik eller fönster >>STAT4 Associates with SLE through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk
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    2009 (Engelska)Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 68, nr 11, s. 1746-1753Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    OBJECTIVES: To confirm and define the genetic association of STAT4 and systemic lupus erythematosus, investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5. METHODS: 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in 5 new sets of cases and controls for replication. STAT4 cDNA was analyzed by 5'-RACE PCR and sequencing. Expression levels were measured by quantitative PCR. RESULTS: In the fine-mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. We also detected transcription of alternative tissue-specific exons 1, indicating presence of tissue-specific promoters of potential importance in the expression of STAT4. No interaction with associated SNPs of IRF5 was observed using regression analysis. CONCLUSIONS: These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. Our results also indicate that both genes STAT4 and IRF5 act additively to increase risk for SLE.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-102290 (URN)10.1136/ard.2008.097642 (DOI)000270700900016 ()19019891 (PubMedID)
    Tillgänglig från: 2009-05-06 Skapad: 2009-05-06 Senast uppdaterad: 2022-01-28Bibliografiskt granskad
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  • 3.
    Abramov, Sergei
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Kazan Fed Univ, Inst Fundamental Med & Biol, Kazan, Russia.
    Kozyrev, Sergey V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Farias, Fabiana H. G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Washington Univ, Genome Inst, Sch Med, St Louis, MO USA.
    Dahlqvist, Johanna
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Leonard, Dag
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wilbe, Maria
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Swedish Univ Agr Sci SLU, Dept Anim Breeding & Genet, Uppsala, Sweden.
    Alexsson, Andrei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pielberg, Gerli
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hansson-Hamlin, H.
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Uppsala, Sweden.
    Andersson, G.
    Swedish Univ Agr Sci SLU, Dept Anim Breeding & Genet, Uppsala, Sweden.
    Tandre, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ronnblom, L.
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Uppsala, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    The risk allele A of rs200395694 associated with SLE in Swedish patients affects on MEF2D gene regulation and alternative splicing2018Ingår i: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 29, nr 12, s. A44-A44Artikel i tidskrift (Övrigt vetenskapligt)
  • 4.
    Adams, Hieab H. H.
    et al.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands..
    Hibar, Derrek P.
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA..
    Chouraki, Vincent
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Univ Lille, RID AGE Risk Factors & Mol Determinants Aging Rel, CHU Lille, Inserm,Inst Pasteur Lille, Lille, France.;Framingham Heart Dis Epidemiol Study, Framingham, MA USA..
    Stein, Jason L.
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA.;Univ N Carolina, Dept Genet, Chapel Hill, NC USA.;Univ N Carolina, UNC Neurosci Ctr, Chapel Hill, NC USA..
    Nyquist, Paul A.
    Johns Hopkins Univ, Dept Neurol, Dept Anesthesia Crit Care Med, Dept Neurosurg, Baltimore, MD 21218 USA..
    Renteria, Miguel E.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia..
    Trompet, Stella
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands..
    Arias-Vasquez, Alejandro
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Seshadri, Sudha
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, Framingham, MA USA..
    Desrivieres, Sylvane
    Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, London, England..
    Beecham, Ashley H.
    Univ Miami, Miller Sch Med, Dept Human Genet, Dr John T Macdonald Fdn, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL 33136 USA..
    Jahanshad, Neda
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA..
    Wittfeld, Katharine
    German Ctr Neurodegenerat Dis DZNE Rostock Greifs, Greifswald, Germany.;Univ Med Greifswald, Dept Psychiat, Greifswald, Germany..
    Van der Lee, Sven J.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Abramovic, Lucija
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Alhusaini, Saud
    McGill Univ, Montreal Neurol Inst, Dept Neurol & Neurosurg, Montreal, PQ, Canada.;Royal Coll Surgeons Ireland, Dublin 2, Ireland..
    Amin, Najaf
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Andersson, Micael
    Umea Univ, Dept Integrat Med Biol, Umea, Sweden.;Umea Univ, Umea Ctr Funct Brain Imaging, Umea, Sweden..
    Arfanakis, Konstantinos
    IIT, Dept Biomed Engn, Chicago, IL 60616 USA.;Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Diagnost Radiol & Nucl Med, Chicago, IL 60612 USA..
    Aribisala, Benjamin S.
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland.;Lagos State Univ, Dept Comp Sci, Lagos, Nigeria.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland..
    Armstrong, Nicola J.
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia.;Murdoch Univ, Math & Stat, Perth, WA, Australia..
    Athanasiu, Lavinia
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway.;Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr, Oslo, Norway..
    Axelsson, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Beiser, Alexa
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Bernard, Manon
    Univ Toronto, Hosp Sick Children, Toronto, ON, Canada..
    Bis, Joshua C.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA..
    Blanken, Laura M. E.
    Erasmus MC, Generat R Study Grp, Rotterdam, Netherlands.;Erasmus MC Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands..
    Blanton, Susan H.
    Univ Miami, Miller Sch Med, Dept Human Genet, Dr John T Macdonald Fdn, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL 33136 USA..
    Bohlken, Marc M.
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Boks, Marco P.
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Bralten, Janita
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Brickman, Adam M.
    Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA.;Columbia Univ, GH Sergievsky Ctr, Med Ctr, New York, NY USA.;Columbia Univ, Dept Neurol, Med Ctr, New York, NY USA..
    Carmichael, Owen
    Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA..
    Chakravarty, M. Mallar
    Douglas Mental Hlth Univ Inst, Cerebral Imaging Ctr, Montreal, PQ, Canada.;McGill Univ, Dept Psychiat & Biomed Engn, Montreal, PQ, Canada..
    Chauhan, Ganesh
    Univ Bordeaux, INSERM Unit U1219, Bordeaux, France..
    Chen, Qiang
    Lieber Inst Brain Dev, Baltimore, MD USA..
    Ching, Christopher R. K.
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA.;Univ Calif Los Angeles, Sch Med, Interdept Neurosci Grad Program, Los Angeles, CA USA..
    Cuellar-Partida, Gabriel
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia..
    Den Braber, Anouk
    Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Doan, Nhat Trung
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway..
    Ehrlich, Stefan
    Tech Univ Dresden, Fac Med, Div Psychol & Social Med & Dev Neurosci, Dresden, Germany.;Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA..
    Filippi, Irina
    Univ Paris Sud, Univ Paris Descartes, NSERM Unit Neuroimaging & Psychiat 1000, Paris, France.;Hosp Cochin, AP HP, Maison Solenn Adolescent Psychopathol & Med Dept, Paris, France..
    Ge, Tian
    Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.;Harvard Med Sch, Boston, MA USA.;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Boston, MA USA..
    Giddaluru, Sudheer
    Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr Psychosis Res, N-5020 Bergen, Norway.;Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway..
    Goldman, Aaron L.
    Lieber Inst Brain Dev, Baltimore, MD USA..
    Gottesman, Rebecca F.
    Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA..
    Greven, Corina U.
    Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Nijmegen, Netherlands.;Karakter Child & Adolescent Psychiat Univ Ctr, Nijmegen, Netherlands.;Kings Coll London, Med Res Council Social, Genet & Dev Psychiat Ctr, Inst Psychol Psychiat & Neurosci, London, England..
    Grimm, Oliver
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Mannheim, Germany..
    Griswold, Michael E.
    Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA..
    Guadalupe, Tulio
    Max Planck Inst Psycholinguist, Language & Genet Dept, Nijmegen, Netherlands.;Int Max Planck Res Sch Language Sci, Nijmegen, Netherlands..
    Hass, Johanna
    Tech Univ Dresden, Fac Med, Dept Child & Adolescent Psychiat, Dresden, Germany..
    Haukvik, Unn K.
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway.;Diakonhjemmet Hosp, Dept Res & Dev, Oslo, Norway..
    Hilal, Saima
    Natl Univ Singapore, Dept Pharmacol, Singapore, Singapore.;Natl Univ Hlth Syst, Mem Aging & Cognit Ctr, Singapore, Singapore..
    Hofer, Edith
    Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, Graz, Austria.;Med Univ Graz, Inst Med Informat Stat & Documentat, Graz, Austria..
    Hoehn, David
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany..
    Holmes, Avram J.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Yale Univ, Dept Psychol, New Haven, CT USA..
    Hoogman, Martine
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Janowitz, Deborah
    Univ Med Greifswald, Dept Psychiat, Greifswald, Germany..
    Jia, Tianye
    Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, London, England..
    Kasperaviciute, Dalia
    UCL, Inst Neurol, London, England.;Epilepsy Soc, Gerrards Cross, Bucks, England.;Imperial Coll London, Dept Med, London, England..
    Kim, Sungeun
    Indiana Univ, Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN USA.;Indiana Univ, Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA..
    Klein, Marieke
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Kraemer, Bernd
    Heidelberg Univ, Dept Gen Psychiat, Sect Expt Psychopathol & Neuroimaging, Heidelberg, Germany..
    Lee, Phil H.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.;Harvard Med Sch, Boston, MA USA.;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Boston, MA USA.;Harvard Med Sch, Massachusetts Gen Hosp, Lurie Ctr Autism, Lexington, MA USA..
    Liao, Jiemin
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore..
    Liewald, David C. M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland..
    Lopez, Lorna M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland..
    Luciano, Michelle
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland..
    Macare, Christine
    Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, London, England..
    Marquand, Andre
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Ctr Cognit Neuroimaging, Nijmegen, Netherlands..
    Matarin, Mar
    UCL, Inst Neurol, London, England.;Epilepsy Soc, Gerrards Cross, Bucks, England.;UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England..
    Mather, Karen A.
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia..
    Mattheisen, Manuel
    Aarhus Univ, Dept Biomed, Aarhus, Denmark.;iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, Aarhus, Denmark.;iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, Copenhagen, Denmark.;Aarhus Univ, iSEQ, Ctr Integrated Sequencing, Aarhus, Denmark..
    Mazoyer, Bernard
    UMR5296 Univ Bordeaux, CNRS, CEA, Bordeaux, France..
    Mckay, David R.
    Yale Univ, Dept Psychiat, New Haven, CT 06520 USA.;Olin Neuropsychiat Res Ctr, Hartford, CT USA..
    McWhirter, Rebekah
    Univ Tasmania, Menzies Inst Med Res, Hobart, Tas, Australia..
    Milaneschi, Yuri
    VU Univ Med Ctr GGZ Geest, EMGO Inst Hlth & Care Res, Dept Psychiat, Amsterdam, Netherlands.;VU Univ Med Ctr GGZ Geest, Neurosci Campus Amsterdam, Amsterdam, Netherlands..
    Mirza-Schreiber, Nazanin
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany..
    Muetzel, Ryan L.
    Erasmus MC, Generat R Study Grp, Rotterdam, Netherlands.;Erasmus MC Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands..
    Maniega, Susana Munoz
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland..
    Nho, Kwangsik
    Indiana Univ, Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN USA.;Indiana Univ, Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN USA.;Indiana Univ, Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA..
    Nugent, Allison C.
    NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA..
    Loohuis, Loes M. Olde
    Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA..
    Oosterlaan, Jaap
    Vrije Univ Amsterdam, Dept Clin Neuropsychol, Amsterdam, Netherlands..
    Papmeyer, Martina
    Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland.;Univ Bern, Univ Hosp Psychiat, Translat Res Ctr, Div Syst Neurosci Psychopathol, CH-3012 Bern, Switzerland..
    Pappa, Irene
    Erasmus MC, Generat R Study Grp, Rotterdam, Netherlands.;Erasmus Univ, Sch Pedag & Educ Sci, Rotterdam, Netherlands..
    Pirpamer, Lukas
    Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, Graz, Austria..
    Pudas, Sara
    Umea Univ, Dept Integrat Med Biol, Umea, Sweden.;Umea Univ, Umea Ctr Funct Brain Imaging, Umea, Sweden..
    Puetz, Benno
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany..
    Rajan, Kumar B.
    Rush Univ, Med Ctr, Rush Inst Healthy Aging, Chicago, IL 60612 USA..
    Ramasamy, Adaikalavan
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England.;Kings Coll London, Dept Med & Mol Genet, London, England.;Univ Oxford, Jenner Inst Labs, Oxford, England..
    Richards, Jennifer S.
    Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Karakter Child & Adolescent Psychiat Univ Ctr, Nijmegen, Netherlands..
    Risacher, Shannon L.
    Indiana Univ, Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN USA.;Indiana Univ, Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA..
    Roiz-Santianez, Roberto
    Univ Cantabria IDIVAL, Sch Med, Dept Med & Psychiat, Univ Hosp Marques de Valdecilla, Santander, Spain.;CIBERSAM Ctr Invest Biomed Red Salud Med, Santander, Spain..
    Rommelse, Nanda
    Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Karakter Child & Adolescent Psychiat Univ Ctr, Nijmegen, Netherlands..
    Rose, Emma J.
    Trinity Coll Dublin, Psychosis Res Grp, Dept Psychiat, Dublin, Ireland.;Trinity Coll Dublin, Trinity Translat Med Inst, Dublin, Ireland..
    Royle, Natalie A.
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland..
    Rundek, Tatjana
    Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth Sci, Miami, FL 33136 USA..
    Saemann, Philipp G.
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany..
    Satizabal, Claudia L.
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, Framingham, MA USA..
    Schmaal, Lianne
    Orygen, Melbourne, Vic, Australia.;Univ Melbourne, Ctr Youth Mental Hlth, Melbourne, Vic, Australia.;Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam, Amsterdam, Netherlands..
    Schork, Andrew J.
    Univ Calif San Diego, Dept Neurosci, Multimodal Imaging Lab, San Diego, CA 92103 USA.;Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92103 USA..
    Shen, Li
    Indiana Univ, Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN USA.;Indiana Univ, Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN USA.;Indiana Univ, Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA..
    Shin, Jean
    Univ Toronto, Hosp Sick Children, Toronto, ON, Canada..
    Shumskaya, Elena
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Ctr Cognit Neuroimaging, Nijmegen, Netherlands..
    Smith, Albert V.
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Sprooten, Emma
    Yale Univ, Dept Psychiat, New Haven, CT 06520 USA.;Olin Neuropsychiat Res Ctr, Hartford, CT USA.;Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland.;Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA..
    Strike, Lachlan T.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia.;Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany..
    Thomson, Russell
    Tordesillas-Gutierrez, Diana
    CIBERSAM Ctr Invest Biomed Red Salud Med, Santander, Spain.;Valdecilla Biomed Res Inst IDIVAL, Neuroimaging Unit, Technol Facil, Santander, Cantabria, Spain..
    Toro, Roberto
    Inst Pasteur, Paris, France..
    Trabzuni, Daniah
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England.;King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh, Saudi Arabia..
    Vaidya, Dhananjay
    Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Ctr, Baltimore, MD 21205 USA..
    Van der Grond, Jeroen
    Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands..
    van der Meer, Dennis
    Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands..
    Van Donkelaar, Marjolein M. J.
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Van Eijk, Kristel R.
    UMC Utrecht, Human Neurogenet Unit, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Van Erp, Theo G. M.
    Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA..
    Van Rooij, Daan
    Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands..
    Walton, Esther
    Tech Univ Dresden, Fac Med, Dept Child & Adolescent Psychiat, Dresden, Germany..
    Westlye, Lars T.
    Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr, Oslo, Norway.;Univ Oslo, Dept Psychol, NORMENT KG Jebsen Ctr, Oslo, Norway..
    Whelan, Christopher D.
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA.;Royal Coll Surgeons Ireland, Dublin 2, Ireland..
    Windham, Beverly G.
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA..
    Winkler, Anderson M.
    Yale Univ, Dept Psychiat, New Haven, CT 06520 USA.;Univ Oxford, FMRIB Ctr, Oxford, England..
    Woldehawariat, Girma
    NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA..
    Wolf, Christiane
    Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, Wurzburg, Germany..
    Wolfers, Thomas
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Xu, Bing
    Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, London, England..
    Yanek, Lisa R.
    Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Ctr, Baltimore, MD 21205 USA..
    Yang, Jingyun
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA..
    Zijdenbos, Alex
    Biospect Inc, Montreal, PQ, Canada..
    Zwiers, Marcel P.
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Ctr Cognit Neuroimaging, Nijmegen, Netherlands..
    Agartz, Ingrid
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway.;Diakonhjemmet Hosp, Dept Res & Dev, Oslo, Norway.;Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden..
    Aggarwal, Neelum T.
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Rush Inst Healthy Aging, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA..
    Almasy, Laura
    Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA.;Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA.;Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA 19104 USA..
    Ames, David
    Royal Melbourne Hosp, Natl Ageing Res Inst, Melbourne, Vic, Australia.;Univ Melbourne, Acad Unit Psychiat Old Age, Melbourne, Vic, Australia..
    Amouyel, Philippe
    Univ Lille, RID AGE Risk Factors & Mol Determinants Aging Rel, CHU Lille, Inserm,Inst Pasteur Lille, Lille, France..
    Andreassen, Ole A.
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway.;Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr, Oslo, Norway..
    Arepalli, Sampath
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Assareh, Amelia A.
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia..
    Barral, Sandra
    Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA..
    Bastin, Mark E.
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland..
    Becker, Diane M.
    Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Ctr, Baltimore, MD 21205 USA..
    Becker, James T.
    Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA.;Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA.;Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA..
    Bennett, David A.
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA..
    Blangero, John
    Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA..
    van Bokhoven, Hans
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Boomsma, Dorret I.
    Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Brodaty, Henry
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia.;UNSW, Dementia Collaborat Res Ctr Assessment & Better, Sydney, NSW, Australia..
    Brouwer, Rachel M.
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Brunner, Han G.
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Maastricht Univ, Med Ctr, Dept Clin Genet, Maastricht, Netherlands..
    Buckner, Randy L.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Harvard Univ, Dept Psychol, Ctr Brain Sci, 33 Kirkland St, Cambridge, MA 02138 USA..
    Buitelaar, Jan K.
    Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Karakter Child & Adolescent Psychiat Univ Ctr, Nijmegen, Netherlands..
    Bulayeva, Kazima B.
    Dagestan State Univ, Dept Evolut & Genet, Makhachkala, Dagestan, Russia..
    Cahn, Wiepke
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Calhoun, Vince D.
    Mind Res Network, Albuquerque, NM USA.;LBERI, Albuquerque, NM USA.;Univ New Mexico, Dept ECE, Albuquerque, NM 87131 USA..
    Cannon, Dara M.
    NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA.;Natl Univ Ireland Galway, Ctr Neuroimaging & Cognit Genom NICOG, NCBES Galway Neurosci Ctr, Coll Med Nursing & Hlth Sci,Clin Neuroimaging Lab, Galway, Ireland..
    Cavalleri, Gianpiero L.
    Royal Coll Surgeons Ireland, Dublin 2, Ireland..
    Chen, Christopher
    Natl Univ Singapore, Dept Pharmacol, Singapore, Singapore.;Natl Univ Hlth Syst, Mem Aging & Cognit Ctr, Singapore, Singapore..
    Cheng, Ching -Yu
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Duke NUS Grad Med Sch, Acad Med Res Inst, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore..
    Cichon, Sven
    Univ Basel, Dept Biomed, Div Med Genet, Basel, Switzerland.;Univ Bonn, Inst Human Genet, Bonn, Germany.;Res Ctr Julich, Inst Neurosci & Med INM1, Julich, Germany..
    Cookson, Mark R.
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Corvin, Aiden
    Trinity Coll Dublin, Psychosis Res Grp, Dept Psychiat, Dublin, Ireland.;Trinity Coll Dublin, Trinity Translat Med Inst, Dublin, Ireland..
    Crespo-Facorro, Benedicto
    Univ Cantabria IDIVAL, Sch Med, Dept Med & Psychiat, Univ Hosp Marques de Valdecilla, Santander, Spain.;CIBERSAM Ctr Invest Biomed Red Salud Med, Santander, Spain..
    Curran, Joanne E.
    Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA..
    Czisch, Michael
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany..
    Dale, Anders M.
    Univ Calif San Diego, Ctr Multimodal Imaging & Genet, San Diego, CA 92103 USA.;Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA.;Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA.;Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA.;Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92103 USA..
    Davies, Gareth E.
    Avera Inst Human Genet, Sioux Falls, SD USA.;Brigham & Womens Hosp, Dept Neurol, Program Translat NeuroPsychiat Gen, 75 Francis St, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    De Geus, Eco J. C.
    Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    De Jager, Philip L.
    Harvard Med Sch, Boston, MA USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Broad Inst, Cambridge, MA USA..
    de Zubicaray, Greig I.
    Queensland Univ Technol, Fac Hlth, Brisbane, Qld, Australia.;Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia..
    Delanty, Norman
    Royal Coll Surgeons Ireland, Dublin 2, Ireland.;Beaumont Hosp, Div Neurol, Dublin 9, Ireland..
    Depondt, Chantal
    Univ Libre Bruxelles, Hop Erasme, Dept Neurol, Brussels, Belgium..
    DeStefano, Anita L.
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway..
    Dillman, Allissa
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Djurovic, Srdjan
    Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr Psychosis Res, N-5020 Bergen, Norway.;Oslo Univ Hosp, Dept Med Genet, Oslo, Norway..
    Donohoe, Gary
    Natl Univ Ireland Galway, Cognit Genet & Cognit Therapy Grp, Neuroimaging Cognit & Genom Ctr NICOG, Galway, Ireland.;Natl Univ Ireland Galway, NCBES Galway Neurosci Ctr, Sch Psychol, Galway, Ireland.;Natl Univ Ireland Galway, Discipline Biochem, Galway, Ireland.;Trinity Coll Dublin, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin 8, Ireland.;Trinity Coll Dublin, Inst Psychiat, Dublin 8, Ireland..
    Drevets, Wayne C.
    NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA.;Janssen Res & Dev LLC, Titusville, NJ USA..
    Duggirala, Ravi
    Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA..
    Dyer, Thomas D.
    Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA..
    Erk, Susanne
    Charite, CCM, Dept Psychiat & Psychotherapy, Berlin, Germany..
    Espeseth, Thomas
    Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr, Oslo, Norway.;Univ Oslo, Dept Psychol, NORMENT KG Jebsen Ctr, Oslo, Norway..
    Evans, Denis A.
    Rush Univ, Med Ctr, Rush Inst Healthy Aging, Chicago, IL 60612 USA..
    Fedko, Iryna
    Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Fernandez, Guillen
    Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Ferrucci, Luigi
    NIA, Intramural Res Program, Baltimore, MD 21224 USA..
    Fisher, Simon E.
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Max Planck Inst Psycholinguist, Language & Genet Dept, Nijmegen, Netherlands..
    Fleischman, Debra A.
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Behav Sci, Chicago, IL 60612 USA..
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland..
    Foroud, Tatiana M.
    Indiana Univ, Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN USA.;Indiana Univ, Sch Med, Med & Mol Genet, Indianapolis, IN USA..
    Fox, Peter T.
    Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA..
    Francks, Clyde
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Max Planck Inst Psycholinguist, Language & Genet Dept, Nijmegen, Netherlands..
    Fukunaga, Masaki
    Natl Inst Physiol Sci, Div Cerebral Integrat, Aichi, Japan..
    Gibbs, J. Raphael
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England.;NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Glahn, David C.
    Yale Univ, Dept Psychiat, New Haven, CT 06520 USA.;Olin Neuropsychiat Res Ctr, Hartford, CT USA..
    Gollub, Randy L.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA.;Harvard Med Sch, Boston, MA USA..
    Goring, Harald H. H.
    Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA.;Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA..
    Grabe, Hans J.
    Univ Med Greifswald, Dept Psychiat, Greifswald, Germany..
    Green, Robert C.
    Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA..
    Gruber, Oliver
    Heidelberg Univ, Dept Gen Psychiat, Sect Expt Psychopathol & Neuroimaging, Heidelberg, Germany..
    Gudnason, Vilmundur
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Guelfi, Sebastian
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England..
    Hansell, Narelle K.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia.;Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Hardy, John
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England..
    Hartman, Catharina A.
    Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands..
    Hashimoto, Ryota
    Osaka Univ, Grad Sch Med, Dept Psychiat, Osaka, Japan.;Osaka Univ, United Grad Sch Child Dev, Mol Res Ctr Childrens Mental Dev, Osaka, Japan..
    Hegenscheid, Katrin
    Univ Med Greifswald, Inst Diagnost Radiol & Neuroradiol, Greifswald, Germany..
    Heinz, Andreas
    Charite, CCM, Dept Psychiat & Psychotherapy, Berlin, Germany..
    Le Hellard, Stephanie
    Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr Psychosis Res, N-5020 Bergen, Norway.;Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway..
    Hernandez, Dena G.
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England.;NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA.;German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany..
    Heslenfeld, Dirk J.
    Vrije Univ Amsterdam, Dept Psychol, Amsterdam, Netherlands..
    Ho, Beng-Choon
    Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA..
    Hoekstra, Pieter J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands..
    Hoffmann, Wolfgang
    German Ctr Neurodegenerat Dis DZNE Rostock Greifs, Greifswald, Germany.;Univ Med Greifswald, Inst Community Med, Greifswald, Germany..
    Hofman, Albert
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Holsboer, Florian
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany.;HMNC Brain Hlth, Munich, Germany..
    Homuth, Georg
    Univ Med Greifswald, Interfac Inst Genet & Funct Gen, Greifswald, Germany..
    Hosten, Norbert
    Univ Med Greifswald, Inst Diagnost Radiol & Neuroradiol, Greifswald, Germany..
    Hottenga, Jouke-Jan
    Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Pol, Hilleke E. Hulshoff
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Ikeda, Masashi
    Fujita Hlth Univ, Sch Med, Dept Psychiat, Toyoake, Aichi, Japan..
    Ikram, M. Kamran
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Natl Univ Singapore, Dept Pharmacol, Singapore, Singapore.;Natl Univ Hlth Syst, Mem Aging & Cognit Ctr, Singapore, Singapore.;Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Duke NUS Grad Med Sch, Acad Med Res Inst, Singapore, Singapore..
    Jack, Clifford R., Jr.
    Mayo Clin, Dept Radiol, Rochester, MN USA..
    Jenldnson, Mark
    Univ Oxford, FMRIB Ctr, Oxford, England..
    Johnson, Robert
    Univ Maryland, Sch Med, NICHD Brain & Tissue Bank Dev Disorders, Baltimore, MD 21201 USA..
    Jonsson, Erik G.
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway.;Univ Oxford, FMRIB Ctr, Oxford, England..
    Jukema, J. Wouter
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands..
    Kahn, Rene S.
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Kanai, Ryota
    Univ Sussex, Sch Psychol, Brighton, E Sussex, England.;UCL, Inst Cognit Neurosci, London, England.;Araya Brain Imaging, Dept Neuroinformat, Tokyo, Japan..
    Kloszewska, Iwona
    Med Univ Lodz, Lodz, Poland..
    Knopman, David S.
    Mayo Clin, Dept Neurol, Rochester, MN USA..
    Kochunov, Peter
    Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21201 USA..
    Kwok, John B.
    Neurosci Res Australia, Sydney, NSW, Australia.;UNSW, Sch Med Sci, Sydney, NSW, Australia..
    Lawrie, Stephen M.
    Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland..
    Lemaitre, Herve
    Univ Paris Sud, Univ Paris Descartes, NSERM Unit Neuroimaging & Psychiat 1000, Paris, France.;Hosp Cochin, AP HP, Maison Solenn Adolescent Psychopathol & Med Dept, Paris, France..
    Liu, Xinmin
    NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA.;Columbia Univ, Med Ctr, New York, NY USA..
    Longo, Dan L.
    NIA, Genet Lab, NIH, Baltimore, MD 21224 USA..
    Longstreth, W. T., Jr.
    Univ Washington, Dept Neurol, Seattle, WA 98195 USA.;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA..
    Lopez, Oscar L.
    Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA.;Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA..
    Lovestone, Simon
    Univ Oxford, Dept Psychiat, Oxford, England.;Kings Coll London, NIHR Dementia Biomed Res Unit, London, England..
    Martinez, Oliver
    Univ Calif Davis, Dept Neurol, Imaging Dementia & Aging IDeA Lab, Sacramento, CA 95817 USA.;Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA..
    Martinot, Jean-Luc
    Univ Paris Sud, Univ Paris Descartes, NSERM Unit Neuroimaging & Psychiat 1000, Paris, France.;Hosp Cochin, AP HP, Maison Solenn Adolescent Psychopathol & Med Dept, Paris, France..
    Mattay, Venkata S.
    Lieber Inst Brain Dev, Baltimore, MD USA.;Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA..
    McDonald, Colm
    Natl Univ Ireland Galway, Ctr Neuroimaging & Cognit Genom NICOG, NCBES Galway Neurosci Ctr, Coll Med Nursing & Hlth Sci,Clin Neuroimaging Lab, Galway, Ireland..
    McIntosh, Andrew M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland..
    McMahon, Katie L.
    Univ Queensland, Ctr Adv Imaging, Brisbane, Qld, Australia..
    McMahon, Francis J.
    NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA..
    Mecocci, Patrizia
    Univ Perugia, Dept Med, Sect Gerontol & Geriatr, Perugia, Italy..
    Melle, Ingrid
    Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway.;Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr, Oslo, Norway..
    Meyer-Lindenberg, Andreas
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Mannheim, Germany..
    Mohnke, Sebastian
    Charite, CCM, Dept Psychiat & Psychotherapy, Berlin, Germany..
    Montgomery, Grant W.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia..
    Morris, Derek W.
    Natl Univ Ireland Galway, Cognit Genet & Cognit Therapy Grp, Neuroimaging Cognit & Genom Ctr NICOG, Galway, Ireland.;Natl Univ Ireland Galway, NCBES Galway Neurosci Ctr, Sch Psychol, Galway, Ireland.;Natl Univ Ireland Galway, Discipline Biochem, Galway, Ireland.;Trinity Coll Dublin, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin 8, Ireland.;Trinity Coll Dublin, Inst Psychiat, Dublin 8, Ireland..
    Mosley, Thomas H.
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA..
    Muhleisen, Thomas W.
    Natl Univ Ireland Galway, Ctr Neuroimaging & Cognit Genom NICOG, NCBES Galway Neurosci Ctr, Coll Med Nursing & Hlth Sci,Clin Neuroimaging Lab, Galway, Ireland.;Res Ctr Julich, Inst Neurosci & Med INM1, Julich, Germany..
    Mueller-Myhsok, Bertram
    Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany.;Munich Cluster Syst Neurol SyNergy, Munich, Germany.;Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England..
    Nalls, Michael A.
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Nauck, Matthias
    Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany.;German Ctr Cardiovasc Res DZHK eV, Partner Site Greifswald, Berlin, Germany..
    Nichols, Thomas E.
    Univ Oxford, FMRIB Ctr, Oxford, England.;Univ Warwick, Dept Stat, Coventry, W Midlands, England.;Univ Warwick, Warwick Mfg Grp, Coventry, W Midlands, England..
    Niessen, Wiro J.
    Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands.;Erasmus MC, Dept Med Informat, Rotterdam, Netherlands.;Delft Univ Technol, Fac Sci Appl, Delft, Netherlands..
    Noethen, Markus M.
    Univ Bonn, Inst Human Genet, Bonn, Germany.;Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany..
    Nyberg, Lars
    Umea Univ, Dept Integrat Med Biol, Umea, Sweden.;Umea Univ, Umea Ctr Funct Brain Imaging, Umea, Sweden..
    Ohi, Kazutaka
    Osaka Univ, Grad Sch Med, Dept Psychiat, Osaka, Japan..
    Olvera, Rene L.
    Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA..
    Ophoff, Roel A.
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands.;Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA..
    Pandolfo, Massimo
    Univ Libre Bruxelles, Hop Erasme, Dept Neurol, Brussels, Belgium..
    Paus, Tomas
    Univ Toronto, Rotman Res Inst, Toronto, ON, Canada.;Univ Toronto, Dept Psychol, Toronto, ON M5S 1A1, Canada.;Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A1, Canada.;Child Mind Inst, New York, NY USA..
    Pausova, Zdenka
    Univ Toronto, Hosp Sick Children, Toronto, ON, Canada.;Univ Toronto, Dept Phys, Toronto, ON, Canada.;Univ Toronto, Dept Nutr Sci, Toronto, ON, Canada..
    Penninx, Brenda W. J. H.
    Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam, Amsterdam, Netherlands..
    Pike, G. Bruce
    Univ Calgary, Dept Radiol, Calgary, AB, Canada.;Univ Calgary, Dept Clin Neurosci, Calgary, AB, Canada..
    Potkin, Steven G.
    Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA..
    Psaty, Bruce M.
    Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.;Univ Washington, Dept Med, Seattle, WA USA.;Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA.;Grp Hlth Res Inst, Grp Hlth, Seattle, WA USA..
    Reppermund, Simone
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia.;UNSW Med, Sch Psychiat, Dept Dev Disabil Neuropsychiat, Kensington, NSW, Australia..
    Rietschel, Marcella
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Mannheim, Germany..
    Roffman, Joshua L.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA..
    Romanczuk-Seiferth, Nina
    Charite, CCM, Dept Psychiat & Psychotherapy, Berlin, Germany..
    Rotter, Jerome I.
    Univ Calif Los Angeles, Med Ctr, Ilnst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst & Pediat Harbor, Torrance, CA 90509 USA..
    Ryten, Mina
    UCL Inst Neurol, Reta Lila Weston Inst, London, England.;UCL Inst Neurol, Dept Mol Neurosci, London, England.;Kings Coll London, Dept Med & Mol Genet, London, England..
    Sacco, Ralph L.
    Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth Sci, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Evelyn F McKnight Brain Inst, Miami, FL 33136 USA..
    Sachdev, Perminder S.
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia.;Prince Wales Hosp, Neuropsychiat Inst, Sydney, NSW, Australia..
    Saykin, Andrew J.
    Indiana Univ, Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN USA.;Indiana Univ, Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA.;Indiana Univ, Sch Med, Med & Mol Genet, Indianapolis, IN USA..
    Schmidt, Reinhold
    Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, Graz, Austria..
    Schofield, Peter R.
    Neurosci Res Australia, Sydney, NSW, Australia.;UNSW, Sch Med Sci, Sydney, NSW, Australia..
    Sigurdsson, Sigurdur
    Iceland Heart Assoc, Kopavogur, Iceland..
    Simmons, Andy
    Kings Coll London, Inst Psychiat, Dept Neuroimaging, London, England.;Kings Coll London, Biomed Res Ctr Mental Hlth, London, England.;Kings Coll London, Biomed Res Unit Dementia, London, England..
    Singleton, Andrew
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Sisodiya, Sanjay M.
    UCL, Inst Neurol, London, England.;Epilepsy Soc, Gerrards Cross, Bucks, England..
    Smith, Colin
    Univ Edinburgh, Acad Dept Neuropathol, Ctr Clin Brain Sci, MRC Edinburgh Brain Bank, Edinburgh, Midlothian, Scotland..
    Smoller, Jordan W.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.;Harvard Med Sch, Boston, MA USA.;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Boston, MA USA..
    Soininen, Hindu.
    Univ Eastern Finland, Inst Clin Med Neurol, Kuopio, Finland.;Kuopio Univ Hosp, Neuroctr Neurol, Kuopio, Finland..
    Srikanth, Velandai
    Peninsula Hlth & Monash Univ, Dept Med, Melbourne, Vic, Australia..
    Steen, Vidar M.
    Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr Psychosis Res, N-5020 Bergen, Norway.;Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway..
    Stott, David J.
    Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Sussmann, Jessika E.
    Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland..
    Thalamuthu, Anbupalam
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia..
    Tiemeier, Henning
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands..
    Toga, Arthur W.
    Univ Southern Calif, Keck Sch Med, Inst Neuroimaging & Informat, Lab Neuro Imaging, Los Angeles, CA USA..
    Traynor, Bryan J.
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Troncoso, Juan
    Johns Hopkins Univ, Brain Resource Ctr, Baltimore, MD USA..
    Turner, Jessica A.
    Georgia State Univ, Atlanta, GA 30303 USA..
    Tzourio, Christophe
    Univ Bordeaux, Institute Neurodegenerat Disorders, CEA, CNRS,UMR 5293, Bordeaux, France..
    Uitterlinden, Andre G.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Hernandez, Maria C. Valdes
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland..
    Van der Brug, Marcel
    Genentech Inc, San Francisco, CA 94080 USA..
    Van der Lugt, Aad
    Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands..
    Van der Wee, Nic J. A.
    Leiden Univ, Med Ctr, Dept Psychiat, Leiden, Netherlands.;Leiden Univ, Med Ctr, Leiden Inst Brain & Cognit, Leiden, Netherlands..
    Van Duijn, Cornelia M.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Van Haren, Neeltje E. M.
    UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Van't Ent, Dennis
    Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Van Tol, Marie Jose
    Univ Groningen, Univ Med Ctr Groningen, Neuroimaging Ctr, Groningen, Netherlands..
    Vardarajan, Badri N.
    Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA..
    Veltman, Dick J.
    Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam, Amsterdam, Netherlands..
    Vernooij, Meike W.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands..
    Voelzke, Henry
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany..
    Walter, Henrik
    Charite, CCM, Dept Psychiat & Psychotherapy, Berlin, Germany..
    Wardlaw, Joanna M.
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland..
    Wassink, Thomas H.
    Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA..
    Weale, Michael E.
    Kings Coll London, Dept Med & Mol Genet, London, England..
    Weinberger, Daniel R.
    Lieber Inst Brain Dev, Baltimore, MD USA.;Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA..
    Weiner, Michael W.
    Univ Calif San Francisco, San Francisco VA Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA 94143 USA..
    Wen, Wei
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia..
    Westman, Eric
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden..
    White, Tonya
    Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands.;Erasmus MC Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands..
    Wong, Tien Y.
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Dagestan State Univ, Dept Evolut & Genet, Makhachkala, Dagestan, Russia.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore..
    Wright, Clinton B.
    Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth Sci, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Evelyn F McKnight Brain Inst, Miami, FL 33136 USA..
    Zielke, H. Ronald
    Univ Maryland, Sch Med, NICHD Brain & Tissue Bank Dev Disorders, Baltimore, MD 21201 USA..
    Zonderman, Alan B.
    NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA..
    Deary, Ian J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland..
    DeCarli, Charles
    Univ Calif Davis, Dept Neurol, Imaging Dementia & Aging IDeA Lab, Sacramento, CA 95817 USA.;Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA..
    Schmidt, Helena
    Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria..
    Martin, Nicholas G.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia..
    De Craen, Anton J. M.
    Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands..
    Wright, Margaret J.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Ctr Adv Imaging, Brisbane, Qld, Australia..
    Launer, Lenore J.
    NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA..
    Schumann, Gunter
    Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, London, England..
    Fornage, Myriam
    Univ Texas Hlth Sci Ctr Houston, Inst Mol Med & Human Genet Ctr, Houston, TX 77030 USA..
    Franke, Barbara
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Debette, Stephanie
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Lieber Inst Brain Dev, Baltimore, MD USA.;Bordeaux Univ Hosp, Dept Neurol, Bordeaux, France..
    Medland, Sarah E.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia..
    Ikram, M. Arfan
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands.;Erasmus MC, Dept Neurol, Rotterdam, Netherlands..
    Thompson, Paul M.
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA.;Univ Western Sydney, Sch Comp Engn & Math, Parramatta, NSW, Australia..
    Novel genetic loci underlying human intracranial volume identified through genome-wide association2016Ingår i: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 19, nr 12, s. 1569-1582Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (rho(genetic) = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N-combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

  • 5. Adoue, Veronique
    et al.
    Schiavi, Alicia
    Light, Nicholas
    Carlsson Almlöf, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lundmark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ge, Bing
    Kwan, Tony
    Caron, Maxime
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Wang, Chuan
    Chen, Shu-Huang
    Goodall, Alison H
    Cambien, Francois
    Deloukas, Panos
    Ouwehand, Willem H
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pastinen, Tomi
    Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs2014Ingår i: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 10, nr 10, s. 754-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Most complex disease-associated genetic variants are located in non-coding regions and are therefore thought to be regulatory in nature. Association mapping of differential allelic expression (AE) is a powerful method to identify SNPs with direct cis-regulatory impact (cis-rSNPs). We used AE mapping to identify cis-rSNPs regulating gene expression in 55 and 63 HapMap lymphoblastoid cell lines from a Caucasian and an African population, respectively, 70 fibroblast cell lines, and 188 purified monocyte samples and found 40-60% of these cis-rSNPs to be shared across cell types. We uncover a new class of cis-rSNPs, which disrupt footprint-derived de novo motifs that are predominantly bound by repressive factors and are implicated in disease susceptibility through overlaps with GWAS SNPs. Finally, we provide the proof-of-principle for a new approach for genome-wide functional validation of transcription factor-SNP interactions. By perturbing NFκB action in lymphoblasts, we identified 489 cis-regulated transcripts with altered AE after NFκB perturbation. Altogether, we perform a comprehensive analysis of cis-variation in four cell populations and provide new tools for the identification of functional variants associated to complex diseases.

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  • 6.
    Afrakhte, Mozhgan
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Growth control mechanisms in normal and neoplastic mammalian cells1998Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The main theme of the studies presented in this thesis is, the growth control mechanisms whose loss in normal cells predispose to or cause cancer. The balance between growth inhibitory and stimulatory mechanisms is crucial for the development and maintenance of a normal animal.

    PDGF, a growth factor for cells of mesenchymal origin, is implicated in normal developmental processes as well as neoplasia. The alternative splicing of exon 6 in PDGF-A gene transcripts gives rise to two different proteins with different compartmentalization properties. The PDGF-A chain homodimers, PDGF-AAL, encoded PDGF A-splice variant remain associated with the cell membrane. Studies of a human fibrosarcoma cell line, U-2197, revealed a high expression level of the cell associated PDGF-AAL which upon release increased autophosphorylation of the endogenous PDGF receptors, suggesting an autocrine loop. PDGF-A gene and PDGFR-α gene found to be co-amplified in the U-2197, indicating an optimised system for growth in these cells, i.e. amplified growth factor receptor as well as a local autocrine supply of the mitogen.

    Members of TGFβ superfamily are potent regulators of the growth and differentiation of a wide range of cell types. Intracellular mediators of TGF-β signalling, SMADs, transduce signals from serine/threonine kinase receptors to the nucleus where they affect transcription of target genes. A new class of SMAD proteins has been identified whose members, the inhibitory SMADS, antagonise TGF-β signals by interfering with agonistic SMADs activity. Smad6 and Smad7 are two closely related TGF-β antagonists identified in mammalian cells. Overexpression of Smad7 inhibited the cellular response to TGF-β whereas expression of an anti-sense Smad7 construct showed an enhancing effect on this response. The inhibitory SMADs may act in a negative feedback loop, as their expression is induced by the same ligands whose action they antagonise.

    Density dependent growth inhibition is a growth control mechanism often lost in transformed and malignant cells. Cells in dense culture are refractory to the mitogen stimulation although, the mitogenic signals were shown to be processed to some extent. The expression of immediate-early genes in dense culture stimulated with mitogen was induced. The activity of cyclin dependent kinases (CDKs), the pivotal kinases in G1/S transition, showed to be density dependent and decreased by increasing cell density. pRb, a tumour suppressor and growth regulatory protein, remained unphosphorylated in mitogen treated dense culture. The cessation of CDKs kinase activity in dense cultures was shown to be accompanied with increasing expression of inhibitory proteins of these kinases, CKIs. The impaired expression of a positive regulator of CDKs, Cdc25A phosphatase, was another feature of dense cultures.

  • 7.
    Agarwal, Prasoon
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Collier, Paul
    Fritz, Markus Hsi-Yang
    Benes, Vladimir
    Wiklund, Helena Jernberg
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Westermark, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Singh, Umashankar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    CGGBP1 mitigates cytosine methylation at repetitive DNA sequences2015Ingår i: BMC Genomics, E-ISSN 1471-2164, Vol. 16, artikel-id 390Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: CGGBP1 is a repetitive DNA-binding transcription regulator with target sites at CpG-rich sequences such as CGG repeats and Alu-SINEs and L1-LINEs. The role of CGGBP1 as a possible mediator of CpG methylation however remains unknown. At CpG-rich sequences cytosine methylation is a major mechanism of transcriptional repression. Concordantly, gene-rich regions typically carry lower levels of CpG methylation than the repetitive elements. It is well known that at interspersed repeats Alu-SINEs and L1-LINEs high levels of CpG methylation constitute a transcriptional silencing and retrotransposon inactivating mechanism. Results: Here, we have studied genome-wide CpG methylation with or without CGGBP1-depletion. By high throughput sequencing of bisulfite-treated genomic DNA we have identified CGGBP1 to be a negative regulator of CpG methylation at repetitive DNA sequences. In addition, we have studied CpG methylation alterations on Alu and L1 retrotransposons in CGGBP1-depleted cells using a novel bisulfite-treatment and high throughput sequencing approach. Conclusions: The results clearly show that CGGBP1 is a possible bidirectional regulator of CpG methylation at Alus, and acts as a repressor of methylation at L1 retrotransposons.

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  • 8.
    Agathangelidis, Andreas
    et al.
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Sutton, Lesley Ann
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Hadzidimitriou, Anastasia
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Tresoldi, Cristina
    IRCCS San Raffaele Sci Inst, Div Immunol Transplantat & Infect, Milan, Italy.
    Langerak, Anton W.
    Erasmus Univ, Med Ctr, Lab Med Immunol, Dept Immunol, Rotterdam, Netherlands.
    Belessi, Chrysoula
    Nikea Gen Hosp, Hematol Dept, Piraeus, Greece.
    Davi, Frederic
    Hop La Pitie Salpetriere, AP HP, Dept Hematol, Paris, France;UPMC Univ Paris 06, UMRS 1138, Paris, France.
    Rosenquist, Richard
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Stamatopoulos, Kostas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Ghia, Paolo
    IRCCS Ist Scientifico San Raffaele, Div Expt Oncol, Milan, Italy;Univ Vita Salute San Raffaele, Milan, Italy.
    Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation2018Ingår i: Journal of Visualized Experiments, E-ISSN 1940-087X, nr 141, artikel-id e57787Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During B cell maturation, the complex process of immunoglobulin (IG) gene V(D)J recombination coupled with somatic hypermutation (SHM) gives rise to a unique DNA sequence within each individual B cell. Since B cell malignancies result from the clonal expansion of a single cell, IG genes represent a unique molecular signature common to all the malignant cells within an individual patient; thus, IG gene rearrangements can be used as clonal markers. In addition to serving as an important clonal identifier, the IG gene sequence can act as a 'molecular timeline' since it is associated with specific developmental stages and hence reflects the history of the B cell involved in the neoplastic transformation. Moreover, for certain malignancies, in particular chronic lymphocytic leukemia (CLL), the IG gene sequence holds prognostic and potentially predictive capabilities. That said, extrapolating meaningful conclusions from IG gene sequence analysis would be impossible if robust methods and tools were not available to aid in their analysis. This article, drawing on the vast experience of the European Research Initiative on CLL (ERIC), details the technical aspects and essential requirements necessary to ensure reliable and reproducible IG gene sequence analysis in CLL, a test that is now recommended for all CLL patients prior to treatment. More specifically, the various analytical stages are described ranging from the identification of the clonotypic IG gene rearrangement and the determination of the nucleotide sequence to the accurate clinical interpretation of the IG gene sequence data.

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  • 9.
    Ahearn, Thomas U.
    et al.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Med Ctr Drive,NIH, Rockville, MD 20850 USA..
    Zhang, Haoyu
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Med Ctr Drive,NIH, Rockville, MD 20850 USA.;Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA..
    Michailidou, Kyriaki
    Inst Neurol & Genet, Biostat Unit, Nicosia, Cyprus.;Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England.;Cyprus Sch Mol Med, Inst Neurol & Genet, Nicosia, Cyprus..
    Milne, Roger L.
    Canc Council Victoria, Canc Epidemiol Div, Melbourne, Vic, Australia.;Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia.;Monash Univ, Sch Clin Sci, Precis Med, Monash Hlth, Clayton, Vic, Australia..
    Bolla, Manjeet K.
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England..
    Dennis, Joe
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England..
    Dunning, Alison M.
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England..
    Lush, Michael
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England..
    Wang, Qin
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England..
    Andrulis, Irene L.
    Mt Sinai Hosp, Fred A Litwin Ctr Canc Genet, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada..
    Anton-Culver, Hoda
    Univ Calif Irvine, Dept Med, Genet Epidemiol Res Inst, Irvine, CA 92717 USA..
    Arndt, Volker
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany..
    Aronson, Kristan J.
    Queens Univ, Dept Publ Hlth Sci, Kingston, ON, Canada.;Queens Univ, Canc Res Inst, Kingston, ON, Canada..
    Auer, Paul L.
    Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1124 Columbia St, Seattle, WA 98104 USA.;Univ Wisconsin, Zilber Sch Publ Hlth, Milwaukee, WI 53201 USA..
    Augustinsson, Annelie
    Lund Univ, Dept Canc Epidemiol, Clin Sci, Lund, Sweden..
    Baten, Adinda
    Univ Hosp Leuven, Leuven Multidisciplinary Breast Ctr, Leuven Canc Inst, Dept Oncol, Leuven, Belgium..
    Becher, Heiko
    Univ Med Ctr Hamburg Eppendorf, Inst Med Biometry & Epidemiol, Hamburg, Germany..
    Behrens, Sabine
    German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany..
    Benitez, Javier
    Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Programme, Madrid, Spain.;Biomed Network Rare Dis CIBERER, Madrid, Spain..
    Bermisheva, Marina
    Russian Acad Sci, Inst Biochem & Genet, Ufa Fed Res Ctr, Ufa, Russia.;St Petersburg State Univ, St Petersburg, Russia..
    Blomqvist, Carl
    Univ Helsinki, Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland.;Örebro Univ Hosp, Dept Oncol, Örebro, Sweden..
    Bojesen, Stig E.
    Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.;Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev, Denmark.;Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Copenhagen Gen Populat Study, Herlev, Denmark..
    Bonanni, Bernardo
    European Inst Oncol IRCCS, Div Canc Prevent & Genet, IEO, Milan, Italy..
    Borresen-Dale, Anne-Lise
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Radiumhosp, Oslo, Norway.;Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway..
    Brauch, Hiltrud
    Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany.;Univ Tubingen, iFIT Cluster Excellence, Tubingen, Germany.;German Canc Consortium DKTK, German Canc Res Ctr DKFZ, Partner Site Tubingen, Tubingen, Germany..
    Brenner, Hermann
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.;German Canc Consortium DKTK, German Canc Res Ctr DKFZ, Heidelberg, Germany.;German Canc Res Ctr, Natl Ctr Tumor Dis NCT, Div Prevent Oncol, Heidelberg, Germany..
    Brooks-Wilson, Angela
    BC Canc Agcy, Genome Sci Ctr, Vancouver, BC, Canada.;Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC, Canada..
    Bruening, Thomas
    Ruhr Univ Bochum IPA, Inst Prevent & Occupa Tional Med, German Social Accid Insurance, Bochum, Germany..
    Burwinkel, Barbara
    German Canc Res Ctr, Mol Epidemiol Grp, C080, Heidelberg, Germany.;Heidelberg Univ, Univ Womens Clin Heidelberg, Mol Biol Breast Canc, Heidelberg, Germany..
    Buys, Saundra S.
    Huntsman Canc Inst, Dept Med, Salt Lake City, UT USA..
    Canzian, Federico
    German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany..
    Castelao, Jose E.
    Xerencia Xest Integrada Vigo SERGAS, Oncol & Genet Unit, Inst Invest Sanitaria Galicia Sur IISGS, Vigo, Spain..
    Chang-Claude, Jenny
    German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany.;Univ Med Ctr Hamburg Eppendorf, Univ Canc Ctr Hamburg UCCH, Canc Epidemiol Grp, Hamburg, Germany..
    Chanock, Stephen J.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Med Ctr Drive,NIH, Rockville, MD 20850 USA..
    Chenevix-Trench, Georgia
    QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Brisbane, Qld, Australia..
    Clarke, Christine L.
    Univ Sydney, Westmead Inst Med Res, Sydney, NSW, Australia..
    Collee, J. Margriet
    Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands..
    Cox, Angela
    Univ Sheffield, Sheffield Inst Nucle Acids SInFoNiA, Dept Oncol & Metab, Sheffield, S Yorkshire, England..
    Cross, Simon S.
    Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield, S Yorkshire, England..
    Czene, Kamila
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Daly, Mary B.
    Fox Chase Canc Ctr, Dept Clin Genet, 7701 Burholme Ave, Philadelphia, PA 19111 USA..
    Devilee, Peter
    Leiden Univ Med Ctr, Dept Human Genet, Leiden, Netherlands.;Leiden Univ Med Ctr, Dept Pathol, Leiden, Netherlands..
    Dork, Thilo
    Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany..
    Dwek, Miriam
    Univ Westminster, Sch Life Sci, London, England..
    Eccles, Diana M.
    Univ Southampton, Fac Med, Southampton, Hants, England..
    Evans, D. Gareth
    Manchester Univ NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester Ctr Genom Med, North West Genom Lab Hub, Manchester, Lancs, England.;Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Biol Med & Hlth, Sch Biol Sci,Div Evolut & Genom Sci, Manchester, Lancs, England..
    Fasching, Peter A.
    Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Comprehens Canc Ctr Erlangen EMN, Erlangen, Germany..
    Figueroa, Jonine
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Canc Res UK Edinburgh Ctr, Edinburgh, Midlothian, Scotland..
    Floris, Giuseppe
    Univ Hosp Leuven, Leuven Multidisciplinary Breast Ctr, Leuven Canc Inst, Dept Oncol, Leuven, Belgium..
    Gago-Dominguez, Manuela
    Complejo Hosp Univ Santiago, Inst Invest Sanitaria Santiago de Compostela IDIS, Fdn Publ Galega Med Xenom, SERGAS, Santiago De Compostela, Spain.;Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA..
    Gapstur, Susan M.
    Amer Canc Soc, Behav & Epidemiol Res Grp, Atlanta, GA 30329 USA..
    Garcia-Saenz, Jose A.
    Hosp Clin San Carlos, Ctr Invest Biomed Red Canc CIBERONC, Inst Invest Sanitaria San Carlos IdISSC, Med Oncol Dept, Madrid, Spain..
    Gaudet, Mia M.
    Amer Canc Soc, Behav & Epidemiol Res Grp, Atlanta, GA 30329 USA..
    Giles, Graham G.
    Canc Council Victoria, Canc Epidemiol Div, Melbourne, Vic, Australia.;Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia.;Monash Univ, Sch Clin Sci, Precis Med, Monash Hlth, Clayton, Vic, Australia..
    Goldberg, Mark S.
    McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ, Canada.;McGill Univ, Dept Med, Montreal, PQ, Canada..
    Gonzalez-Neira, Anna
    Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Programme, Madrid, Spain..
    Alnaes, Grethe I. Grenaker
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Radiumhosp, Oslo, Norway..
    Grip, Mervi
    Univ Oulu, Oulu Univ Hosp, Dept Surg, Oulu, Finland..
    Guenel, Pascal
    Univ Paris Saclay, Ctr Res Epidemiol & Populat Hlth CESP, INSERM, Team Exposome & Hered, Villejuif, France..
    Haiman, Christopher A.
    Univ Southern Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90007 USA..
    Hall, Per
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Soder Sjukhuset, Dept Oncol, Stockholm, Sweden..
    Hamann, Ute
    German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany..
    Harkness, Elaine F.
    Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Biol Med & Hlth, Div Informat Imaging & Data Sci, Manchester, Lancs, England.;Manchester Univ NHS Fdn Trust, Wythenshawe Hosp, Nightingale & Genesis Prevent Ctr, Manchester, Lancs, England.;Manchester Univ NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, NIHR Manchester Biomed Res Unit, Manchester, Lancs, England..
    Heemskerk-Gerritsen, Bernadette A. M.
    Erasmus MC Canc Inst, Dept Med Oncol, Rotterdam, Netherlands..
    Holleczek, Bernd
    Saarland Canc Registry, Saarbrucken, Germany..
    Hollestelle, Antoinette
    Erasmus MC Canc Inst, Dept Med Oncol, Rotterdam, Netherlands..
    Hooning, Maartje J.
    Erasmus MC Canc Inst, Dept Med Oncol, Rotterdam, Netherlands..
    Hoover, Robert N.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Med Ctr Drive,NIH, Rockville, MD 20850 USA..
    Hopper, John L.
    Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia..
    Howell, Anthony
    Univ Manchester, Div Canc Sci, Manchester, Lancs, England..
    Jakimovska, Milena
    MASA, Res Ctr Genet Engn & Biotechnol Georgi D Efremov, Skopje, North Macedonia..
    Jakubowska, Anna
    Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland.;Pomeranian Med Univ, Independent Lab Mol Biol & Genet Diagnost, Szczecin, Poland..
    John, Esther M.
    Stanford Univ, Dept Epidemiol & Populat Hlth, Sch Med, Stanford, CA 94305 USA.;Stanford Univ, Stanford Canc Inst, Dept Med, Div Oncol,Sch Med, Stanford, CA 94305 USA..
    Jones, Michael E.
    Inst Canc Res, Div Genet & Epidemiol, London, England..
    Jung, Audrey
    German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany..
    Kaaks, Rudolf
    German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany..
    Kauppila, Saila
    Univ Oulu, Oulu Univ Hosp, Depart Ment Pathol, Oulu, Finland..
    Keeman, Renske
    Antoni Van Leeuwenhoek Hosp, Div Mol Pathol, Netherlands Canc Inst, Amsterdam, Netherlands..
    Khusnutdinova, Elza
    Russian Acad Sci, Inst Biochem & Genet, Ufa Fed Res Ctr, Ufa, Russia.;Bashkir State Univ, Dept Genet & Fundamental Med, Ufa, Russia..
    Kitahara, Cari M.
    NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Ko, Yon-Dschun
    Johanniter Krankenhaus, Dept Internal Med, Johanniter Kliniken Bonn, Bonn, Germany..
    Koutros, Stella
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Med Ctr Drive,NIH, Rockville, MD 20850 USA..
    Kristensen, Vessela N.
    Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway.;Oslo Univ Hosp, Dept Med Genet, Oslo, Norway.;Univ Oslo, Oslo, Norway..
    Kruger, Ute
    Lund Univ, Dept Canc Epidemiol, Clin Sci, Lund, Sweden..
    Kubelka-Sabit, Katerina
    Clin Hosp Acibadem Sistina, Dept Histopathol & Cytol, Skopje, North Macedonia..
    Kurian, Allison W.
    Stanford Univ, Dept Epidemiol & Populat Hlth, Sch Med, Stanford, CA 94305 USA.;Stanford Univ, Stanford Canc Inst, Dept Med, Div Oncol,Sch Med, Stanford, CA 94305 USA..
    Kyriacou, Kyriacos
    Cyprus Sch Mol Med, Inst Neurol & Genet, Nicosia, Cyprus.;Cyprus Inst Neurol & Genet, Canc Genet Therapeut & Ultrastruct Pathol, Nicosia, Cyprus..
    Lambrechts, Diether
    Univ Leuven, Dept Human Genet, Lab Translat Genet, Leuven, Belgium.;VIB Ctr Canc Biol, Leuven, Belgium..
    Lee, Derrick G.
    BC Canc, Canc Control Res, Vancouver, BC, Canada.;St Francis Xavier Univ, Dept Math & Stat, Antigonish, NS, Canada..
    Lindblom, Annika
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden..
    Linet, Martha
    NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Lissowska, Jolanta
    M Sklodowska Curie Natl Res Inst Oncol, Dept Canc Epidemiol Ogy & Prevent, Warsaw, Poland..
    Llaneza, Ana
    Hosp Univ Cent Asturias, Gen & Gastroenterol Surg Serv, Oviedo, Spain..
    Lo, Wing-Yee
    Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany.;Univ Tubingen, Tubingen, Germany..
    MacInnis, Robert J.
    Canc Council Victoria, Canc Epidemiol Div, Melbourne, Vic, Australia.;Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia..
    Mannermaa, Arto
    Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland.;Univ Eastern Finland, Translat Canc Res Area, Kuopio, Finland.;Kuopio Univ Hosp, Biobank Eastern Finland, Kuopio, Finland..
    Manoochehri, Mehdi
    German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany..
    Margolin, Sara
    Soder Sjukhuset, Dept Oncol, Stockholm, Sweden.;Karolinska Inst, Dept Clin Sci & Educ, Sodersjukhuset Stockholm, Stockholm, Sweden..
    Martinez, Maria Elena
    Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA..
    McLean, Catriona
    Alfred Hosp, Anat Pathol, Melbourne, Vic, Australia..
    Meindl, Alfons
    Univ Munich, Dept Gynecol & Obstet, Campus Grosshadern, Munich, Germany..
    Menon, Usha
    UCL, Inst Clin Trials & Methodol, London, England..
    Nevanlinna, Heli
    Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland..
    Newman, William G.
    Manchester Univ NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester Ctr Genom Med, North West Genom Lab Hub, Manchester, Lancs, England.;Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Biol Med & Hlth, Sch Biol Sci,Div Evolut & Genom Sci, Manchester, Lancs, England..
    Nodora, Jesse
    Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA.;Univ Calif San Diego, Herbert Wertheim Sch Publ Hlth & Human Longev Sci, La Jolla, CA 92093 USA..
    Offit, Kenneth
    Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, Clin Genet Res Lab, 1275 York Ave, New York, NY 10021 USA..
    Olsson, Hakan
    Lund Univ, Dept Canc Epidemiol, Clin Sci, Lund, Sweden..
    Orr, Nick
    Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast, North Ireland..
    Park-Simon, Tjoung-Won
    Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany..
    Patel, Alpa, V
    Amer Canc Soc, Behav & Epidemiol Res Grp, Atlanta, GA 30329 USA..
    Peto, Julian
    Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England..
    Pita, Guillermo
    Spanish Natl Canc Res Ctr, Human Genotyping CEGEN Unit, Human Canc Genet Program, Madrid, Spain..
    Plaseska-Karanfilska, Dijana
    MASA, Res Ctr Genet Engn & Biotechnol Georgi D Efremov, Skopje, North Macedonia..
    Prentice, Ross
    Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1124 Columbia St, Seattle, WA 98104 USA..
    Punie, Kevin
    Univ Hosp Leuven, Leuven Canc Inst, Dept Gen Med Oncol, Leuven, Belgium.;Univ Hosp Leuven, Multidisciplinary Breast Ctr, Leuven Canc Inst, Leuven, Belgium..
    Pylkas, Katri
    Univ Oulu, Bioctr Oulu, Canc & Translat Med Res Unit, Lab Canc Genet & Tumor Biol, Oulu, Finland.;Northern Finland Lab Ctr Oulu, Lab Canc Genet & Tumor Biol, Oulu, Finland..
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Dept Res, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy..
    Rennert, Gad
    Carmel Hosp, Clalit Natl Canc Control Ctr, Technion Fac Med, Haifa, Israel..
    Romero, Atocha
    Hosp Univ Puerta de Hierro, Med Oncol Dept, Madrid, Spain..
    Ruediger, Thomas
    Staedt Klinikum Karlsruhe, Inst Pathol, Karlsruhe, Germany..
    Saloustros, Emmanouil
    Univ Hosp Larissa, Dept Oncol, Larisa, Greece..
    Sampson, Sarah
    Manchester Univ NHS Fdn Trust, Prevent Breast Canc Ctr, Manchester, Lancs, England.;Manchester Univ NHS Fdn Trust, Nightingale Breast Screening Ctr, Manchester, Lancs, England..
    Sandler, Dale P.
    NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA..
    Sawyer, Elinor J.
    Kings Coll London, Comprehens Canc Ctr, Sch Canc & Pharmaceut Sci, Guys Campus, London, England..
    Schmutzler, Rita K.
    Univ Cologne, Univ Hosp Cologne, Fac Med, Ctr Integrated Oncol CIO, Cologne, Germany.;Univ Cologne, Univ Hosp Cologne, Fac Med, Ctr Mol Med Cologne CMMC, Cologne, Germany.;Univ Cologne, Univ Hosp Cologne, Fac Med, Ctr Familial Breast & Ovarian Canc, Cologne, Germany..
    Schoemaker, Minouk J.
    Inst Canc Res, Div Genet & Epidemiol, London, England..
    Schottker, Ben
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.;Heidelberg Univ, Network Aging Res, Heidelberg, Germany..
    Sherman, Mark E.
    Mayo Clin, Dept Hlth Sci Res, Coll Med, Jacksonville, FL USA..
    Shu, Xiao-Ou
    Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Vanderbilt Ingram Canc Ctr, Dept Med,Sch Med, Nashville, TN USA..
    Smichkoska, Snezhana
    Ss Cyril & Methodius Univ Skopje, Univ Clin Radiotherapy & Oncol, Med Fac, Skopje, North Macedonia..
    Southey, Melissa C.
    Canc Council Victoria, Canc Epidemiol Div, Melbourne, Vic, Australia.;Monash Univ, Sch Clin Sci, Precis Med, Monash Hlth, Clayton, Vic, Australia.;Univ Melbourne, Dept Clin Pathol, Melbourne, Vic, Australia..
    Spinelli, John J.
    BC Canc, Populat Oncol, Vancouver, BC, Canada.;Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC, Canada..
    Swerdlow, Anthony J.
    Inst Canc Res, Div Genet & Epidemiol, London, England.;Inst Canc Res, Div Breast Canc Res, London, England..
    Tamimi, Rulla M.
    Weill Cornell Med, Dept Populat Hlth Sci, New York, NY USA..
    Tapper, William J.
    Univ Southampton, Fac Med, Southampton, Hants, England..
    Taylor, Jack A.
    NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA.;NIEHS, Epigenet & Stem Cell Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA..
    Teras, Lauren R.
    Amer Canc Soc, Behav & Epidemiol Res Grp, Atlanta, GA 30329 USA..
    Terry, Mary Beth
    Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA..
    Torres, Diana
    German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany.;Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia..
    Troester, Melissa A.
    Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA.;Univ N Carolina, UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA..
    Vachon, Celine M.
    Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN USA..
    van Deurzen, Carolien H. M.
    Erasmus MC, Dept Pathol, Rotterdam, Netherlands..
    van Veen, Elke M.
    Manchester Univ NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester Ctr Genom Med, North West Genom Lab Hub, Manchester, Lancs, England.;Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Biol Med & Hlth, Sch Biol Sci,Div Evolut & Genom Sci, Manchester, Lancs, England..
    Wagner, Philippe
    Lund Univ, Dept Canc Epidemiol, Clin Sci, Lund, Sweden..
    Weinberg, Clarice R.
    NIEHS, Biostat & Computat Biol Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA..
    Wendt, Camilla
    Soder Sjukhuset, Dept Oncol, Stockholm, Sweden.;Karolinska Inst, Dept Clin Sci & Educ, Sodersjukhuset Stockholm, Stockholm, Sweden..
    Wesseling, Jelle
    Antoni Van Leeuwenhoek Hosp, Div Mol Pathol, Netherlands Canc Inst, Amsterdam, Netherlands.;Antoni Van Leeuwenhoek Hosp, Dept Pathol, Netherlands Canc Inst, Amsterdam, Netherlands..
    Winqvist, Robert
    Univ Oulu, Bioctr Oulu, Canc & Translat Med Res Unit, Lab Canc Genet & Tumor Biol, Oulu, Finland.;Northern Finland Lab Ctr Oulu, Lab Canc Genet & Tumor Biol, Oulu, Finland..
    Wolk, Alicja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Medicinsk epidemiologi. Karolinska Inst, Inst Environm Med, Stockholm, Sweden..
    Yang, Xiaohong R.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Med Ctr Drive,NIH, Rockville, MD 20850 USA..
    Zheng, Wei
    Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Vanderbilt Ingram Canc Ctr, Dept Med,Sch Med, Nashville, TN USA..
    Couch, Fergus J.
    Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA..
    Simard, Jacques
    Univ Laval, Res Ctr, Ctr Hosp Univ Quebec, Dept Mol Med,Genom Ctr, Quebec City, PQ, Canada..
    Kraft, Peter
    Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA.;Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA..
    Easton, Douglas F.
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England.;Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England..
    Pharoah, Paul D. P.
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England.;Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England..
    Schmidt, Marjanka K.
    Antoni Van Leeuwenhoek Hosp, Div Mol Pathol, Netherlands Canc Inst, Amsterdam, Netherlands.;Antoni Van Leeuwenhoek Hosp, Div Psychosocial Res & Epidemiol, Netherlands Canc Inst, Amsterdam, Netherlands..
    Garcia-Closas, Montserrat
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Med Ctr Drive,NIH, Rockville, MD 20850 USA..
    Chatterjee, Nilanjan
    Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA.;Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA..
    Common variants in breast cancer risk loci predispose to distinct tumor subtypes2022Ingår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 24, nr 1, artikel-id 2Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.

    Methods

    Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.

    Results

    Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions.

    Conclusion

    This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.

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    FULLTEXT01
  • 10.
    Ahlford, Annika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Applications of Four-Colour Fluorescent Primer Extension Technology for SNP Analysis and Discovery2010Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Studies on genetic variation can reveal effects on traits and disease, both in humans and in model organisms. Good technology for the analysis of DNA sequence variations is critical. Currently the development towards assays for large-scale and parallel DNA sequencing and genotyping is progressing rapidly. Single base primer extension (SBE) is a robust reaction principle based on four-colour fluorescent terminating nucleotides to interrogate all four DNA nucleotides in a single reaction. In this thesis, SBE methods were applied to the analysis and discovery of single nucleotide polymorphism (SNP) in the model organism Drosophila melanogaster and in humans.

    The tag-array minisequencing system in a microarray format is convenient for intermediate sized genotyping projects. The system is scalable and flexible to adapt to specialized and novel applications. In Study I of the thesis a tool was established to automate quality control of clustered genotype data. By calculating “Silhouette scores”, the SNP genotype assignment can be evaluated by a single numeric measure. Silhouette scores were then applied in Study I to compare the performance of four DNA polymerases and in Study III to evaluate freeze-dried reagents in the tag-array minisequencing system.

    The characteristics of the tag-array minisequencing system makes it suitable for inexpensive genome-wide gene mapping in the fruit fly. In Study II a high-resolution SNP map, and 293 genotyping assays, were established across the X, 2nd and 3rd chromosomes to distinguish commonly used Drosophila strains. A database of the SNP markers and a program for automatic allele calling and identification of map positions of mutants was also developed. The utility of the system was demonstrated by rapid mapping of 14 genes that disrupt embryonic muscle patterning.

    In Study III the tag-array minisequencing system was adapted to a lab-on-a-chip format for diagnostic testing for mutations in the TP53 gene. Freeze-drying was evaluated for storing reagents, including thermo-sensitive enzymes, on the microchip to reduce the complexity of the integrated test. Correct genotyping results were obtained using freeze-dried reagents in each reaction step of the genotyping protocol, both in test tubes and in single polymer test chambers. The results showed the potential of the approach to be implemented in fully integrated systems.

    The four-colour chemistry of SBE has been developed further to allow massively parallel sequencing (MPS) of short DNA fragments as in the Genome Analyzer system (Solexa/Illumina). In Study IV MPS was used to compare Nimblegen arrays and the SureSelect solution-based system for targeted enrichment of 56 continuous human candidate-gene regions totalling 3.1 Mb in size. Both methods detected known SNPs and discovered novel SNPs in the target regions, demonstrating the feasibility for complexity reduction of sequencing libraries by hybridization methods.

    Delarbeten
    1.
    Posten kunde inte hittas. Det kan bero på att posten inte längre är tillgänglig eller att du har råkat ange ett felaktigt id i adressfältet.
    2. High-resolution, high-throughput SNP mapping in Drosophila melanogaster
    Öppna denna publikation i ny flik eller fönster >>High-resolution, high-throughput SNP mapping in Drosophila melanogaster
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    2008 (Engelska)Ingår i: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 5, nr 4, s. 323-329Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Single nucleotide polymorphisms (SNPs) are useful markers for genetic mapping experiments in model organisms. Here we report the establishment of a high-density SNP map and high-throughput genotyping assays for Drosophila melanogaster. Our map comprises 27,367 SNPs in common laboratory Drosophila stocks. These SNPs were clustered within 2,238 amplifiable markers at an average density of 1 marker every 50.3 kb, or 6.3 genes. We have also constructed a set of 62 Drosophila stocks, each of which facilitates the generation of recombinants within a defined genetic interval of 1-2 Mb. For flexible, high-throughput SNP genotyping, we used fluorescent tag-array mini-sequencing (TAMS) assays. We designed and validated TAMS assays for 293 SNPs at an average resolution of 391.3 kb, and demonstrated the utility of these tools by rapidly mapping 14 mutations that disrupt embryonic muscle patterning. These resources enable high-resolution high-throughput genetic mapping in Drosophila.

    Nyckelord
    Animals, Chromosome Mapping, Drosophila melanogaster/embryology/*genetics, Genome; Insect, Muscle Development/*genetics, Mutation, Polymorphism; Single Nucleotide
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-16561 (URN)10.1038/nmeth.1191 (DOI)000254559400019 ()18327265 (PubMedID)
    Tillgänglig från: 2008-05-28 Skapad: 2008-05-28 Senast uppdaterad: 2022-01-28Bibliografiskt granskad
    3. Positional cloning by fast-track SNP-mapping in Drosophila melanogaster
    Öppna denna publikation i ny flik eller fönster >>Positional cloning by fast-track SNP-mapping in Drosophila melanogaster
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    2008 (Engelska)Ingår i: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 3, nr 11, s. 1751-1765Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Positional cloning of chemically induced mutations is the rate-limiting step in forward genetic screens in Drosophila. Single-nucleotide polymorphisms (SNPs) are useful markers to locate a mutated region in the genome. Here, we provide a protocol for high-throughput, high-resolution SNP mapping that enables rapid and cost-effective positional cloning in Drosophila. In stage 1 of the protocol, we use highly multiplexed tag-array mini-sequencing assays to map mutations to an interval of 1-2 Mb. In these assays, SNPs are genotyped by primer extension using fluorescently labeled dideoxy-nucleotides. Fluorescent primers are captured and detected on a microarray. In stage 2, we selectively isolate recombinants within the identified 1-2 Mb interval for fine mapping of mutations to about 50 kb. We have previously demonstrated the applicability of this protocol by mapping 14 muscle morphogenesis mutants within 4 months, which represents a significant acceleration compared with other commonly used mapping strategies that may take years.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-98390 (URN)10.1038/nprot.2008.175 (DOI)000265781600008 ()18948975 (PubMedID)
    Tillgänglig från: 2009-02-20 Skapad: 2009-02-20 Senast uppdaterad: 2022-01-28Bibliografiskt granskad
    4. Dried reagents for multiplex genotyping by tag-array minisequencing to be used in microfluidic devices
    Öppna denna publikation i ny flik eller fönster >>Dried reagents for multiplex genotyping by tag-array minisequencing to be used in microfluidic devices
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    2010 (Engelska)Ingår i: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 135, nr 9, s. 2377-2385Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    We present an optimized procedure for freeze-drying and storing reagents for multiplex PCR followed by genotyping using a tag-array minisequencing assay with four color fluorescence detection which is suitable for microfluidic assay formats. A test panel was established for five cancer mutations in three codons (175, 248 and 273) of the tumor protein gene (TP53) and for 13 common single nucleotide polymorphisms (SNPs) in the TP53 gene. The activity of DNA polymerase was preserved for six months of storage after freeze-drying, and the half-life of activities of exonuclease I and shrimp alkaline phosphatase were estimated to 55 and 200 days, respectively. We conducted a systematic genotyping comparison using freeze-dried and liquid reagents. The accuracy of successful genotyping was 99.1% using freeze-dried reagents compared to liquid reagents. As a proof of concept, the genotyping protocol was carried out with freeze-dried reagents stored in reaction chambers fabricated by micromilling in a cyclic olefin copolymer substrate. The results reported in this study are a key step towards the development of an integrated microfluidic device for point-of-care DNA-based diagnostics.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-129216 (URN)10.1039/c0an00321b (DOI)000281007300027 ()20668755 (PubMedID)
    Tillgänglig från: 2010-08-09 Skapad: 2010-08-09 Senast uppdaterad: 2022-01-28Bibliografiskt granskad
    5.
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    Ladda ner fulltext (pdf)
    FULLTEXT01
  • 11.
    Ahluwalia, Tarunveer S.
    et al.
    Steno Diabet Ctr Copenhagen, DK-2820 Gentofte, Denmark.;Univ Copenhagen, Bioinformat Ctr, Dept Biol, DK-2200 Copenhagen, Denmark..
    Prins, Bram P.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands..
    Abdollahi, Mohammadreza
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands..
    Armstrong, Nicola J.
    Murdoch Univ, Math & Stat, Perth, WA 6150, Australia..
    Aslibekyan, Stella
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35233 USA..
    Bain, Lisa
    QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia..
    Jefferis, Barbara
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Primary Care & Populat Hlth, London NW3 2PF, England..
    Baumert, Jens
    Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany..
    Beekman, Marian
    Leiden Univ Med Ctr, Dept Biomed Data Sci, Sect Mol Epidemiol, NL-2300 RC Leiden, Netherlands..
    Ben-Shlomo, Yoav
    Univ Bristol, Populat Hlth Sci, Bristol BS8 2PS, Avon, England..
    Bis, Joshua C.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA..
    Mitchell, Braxton D.
    Univ Maryland, Dept Med, Sch Med, Baltimore, MD 21202 USA..
    de Geus, Eco
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Amsterdam Univ Med Ctr, Amsterdam Publ Hlth Res Inst, NL-1105 AZ Amsterdam, Netherlands..
    Delgado, Graciela E.
    Heidelberg Univ, Med Fac Mannheim, Dept Med Nephrol Hypertensiol Rheumatol Endocrino, D-68167 Mannheim, Germany..
    Marek, Diana
    SIB Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland..
    Eriksson, Joel
    Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res CBAR, Dept Internal Med & Clin Nutr, S-41345 Gothenburg, Sweden..
    Kajantie, Eero
    Natl Inst Hlth & Welf, Chron Dis Prevent Unit, POB 30, Helsinki 00271, Finland.;Helsinki Univ Cent Hosp, Hosp Children & Adolescents, Helsinki 00014, Finland.;Univ Helsinki, Helsinki 00014, Finland..
    Kanoni, Stavroula
    Queen Mary Univ London, Barts & London Med Sch, William Harvey Res Inst, London EC1M 6BQ, England..
    Kemp, John P.
    Univ Queensland, Univ Queensland Diamantina Inst, Woolloongabba, Qld 4102, Australia.;Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Lu, Chen
    Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02118 USA..
    Marioni, Riccardo E.
    Univ Edinburgh, Ctr Genom & Expt Med, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland..
    McLachlan, Stela
    Univ Edinburgh, Usher Inst, Edinburgh EH8 9AG, Midlothian, Scotland..
    Milaneschi, Yuri
    Vrije Univ, Dept Psychiat, Amsterdam UMC, NL-1081 HJ Amsterdam, Netherlands..
    Nolte, Ilja M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands..
    Petrelis, Alexandros M.
    Univ Lorraine, IGE PCV, INSERM, F-54000 Nancy, France..
    Porcu, Eleonora
    CNR, Ist Ric Genet & Biomed, I-09042 Monserrato, CA, Italy..
    Sabater-Lleal, Maria
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Cardiovasc Med, S-17176 Stockholm, Sweden.;Inst Invest Biomed St Pau IIB St Pau, Unit Genom Complex Dis, Barcelona 08041, Spain..
    Naderi, Elnaz
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands..
    Seppala, Ilkka
    Tampere Univ, Fac Med & Hlth Technol, Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Tampere Univ, Fac Med & Hlth Technol, Finnish Cardiovasc Res Ctr Tampere, Tampere 33520, Finland..
    Shah, Tina
    UCL, Inst Cardiovasc Sci, London WC1E 6BT, England..
    Singhal, Gaurav
    Univ Adelaide, Adelaide Med Sch, Discipline Psychiat, Adelaide, SA 5005, Australia..
    Standl, Marie
    Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany..
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany..
    Thalamuthu, Anbupalam
    Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW 2052, Australia..
    Thiering, Elisabeth
    Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Dr von Hauner Childrens Hosp, Div Metab Dis & Nutr Med, D-80337 Munich, Germany..
    Trompet, Stella
    Leiden Univ Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands.;Leiden Univ Med Ctr, Dept Internal Med, Sect Gerontol & Geriatr, NL-2333 ZA Leiden, Netherlands..
    Ballantyne, Christie M.
    Baylor Coll Med, Houston, TX 77030 USA..
    Benjamin, Emelia J.
    Natl Heart Lung & Blood Inst, Framingham, MA 01702 USA.;Boston Univ, Framingham Heart Study, Framingham, MA 01702 USA.;Boston Univ, Dept Med, Sect Cardiovasc Med & Prevent Med, Sch Med, Boston, MA 02118 USA..
    Casas, Juan P.
    VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA 02130 USA..
    Toben, Catherine
    Univ Adelaide, Adelaide Med Sch, Discipline Psychiat, Adelaide, SA 5005, Australia..
    Dedoussis, George
    Harokopio Univ, Dept Nutr Dietet, Athens 17671, Greece..
    Deelen, Joris
    Leiden Univ Med Ctr, Dept Biomed Data Sci, Sect Mol Epidemiol, NL-2300 RC Leiden, Netherlands.;Max Planck Inst Biol Ageing, D-50931 Cologne, Germany..
    Durda, Peter
    Univ Vermont, Larner Coll Med, Dept Pathol & Lab Med, Burlington, VT 05405 USA..
    Engmann, Jorgen
    UCL, Inst Cardiovasc Sci, London WC1E 6BT, England..
    Feitosa, Mary F.
    Washington Univ, Dept Genet, Div Stat Genom, Sch Med, St Louis, MO 63110 USA..
    Grallert, Harald
    Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany.;German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany..
    Hammarstedt, Ann
    Univ Gothenburg, Dept Mol & Clin Med, Lundberg Lab Diabet Res, Sahlgrenska Acad, SE-41345 Gothenburg, Sweden..
    Harris, Sarah E.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Homuth, Georg
    Univ Med Greifswald, Interfac Inst Genet & Funct Genom, D-17475 Greifswald, Germany..
    Hottenga, Jouke-Jan
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Amsterdam Univ Med Ctr, Amsterdam Publ Hlth Res Inst, NL-1105 AZ Amsterdam, Netherlands..
    Jalkanen, Sirpa
    Univ Turku, MediCity Res Lab, Turku 20520, Finland.;Univ Turku, Dept Med Microbiol & Immunol, Turku 20520, Finland..
    Jamshidi, Yalda
    St Georges Univ London, Mol & Clin Sci Inst, Genet Res Ctr, London SW17 0RE, England..
    Jawahar, Magdalene C.
    Univ Adelaide, Adelaide Med Sch, Discipline Psychiat, Adelaide, SA 5005, Australia..
    Jess, Tine
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark..
    Kivimaki, Mika
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London WC1E 7HB, England..
    Kleber, Marcus E.
    Heidelberg Univ, Med Fac Mannheim, Dept Med Nephrol Hypertensiol Rheumatol Endocrino, D-68167 Mannheim, Germany..
    Lahti, Jari
    Univ Turku, Turku Inst Adv Studies, Turku 20014, Finland.;Univ Helsinki, Dept Psychol & Logoped, Helsinki 00014, Finland..
    Liu, Yongmei
    Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC 27157 USA..
    Marques-Vidal, Pedro
    Lausanne Univ Hosp CHUV, Dept Internal Med, CH-1011 Lausanne, Switzerland.;Univ Lausanne, CH-1011 Lausanne, Switzerland..
    Mellstrom, Dan
    Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res CBAR, Dept Internal Med & Clin Nutr, S-41345 Gothenburg, Sweden..
    Mooijaart, Simon P.
    Leiden Univ Med Ctr, Dept Internal Med, Sect Gerontol & Geriatr, NL-2333 ZA Leiden, Netherlands..
    Muller-Nurasyid, Martina
    Ludwig Maximilians Univ LMU Munich, Fac Med, IBE, D-81377 Munich, Germany.;Johhanes Gutenberg Univ, Univ Med Ctr, Inst Med Biostat Epidemiol & Informat IMBEI, D-55101 Mainz, Germany..
    Penninx, Brenda
    Vrije Univ, Dept Psychiat, Amsterdam UMC, NL-1081 HJ Amsterdam, Netherlands..
    Revez, Joana A.
    QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia..
    Rossing, Peter
    Steno Diabet Ctr Copenhagen, DK-2820 Gentofte, Denmark.;Univ Copenhagen, Dept Clin Med, DK-2200 Copenhagen, Denmark..
    Raikkonen, Katri
    Univ Helsinki, Dept Psychol & Logoped, Helsinki 00014, Finland..
    Sattar, Naveed
    BHF Glasgow Cardiovasc Res Ctr, Fac Med, Glasgow G12 8TA, Lanark, Scotland..
    Scharnagl, Hubert
    Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, A-8036 Graz, Austria..
    Sennblad, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Ctr Mol Med, Dept Med Solna, Cardiovasc Med, S-17176 Stockholm, Sweden.
    Silveira, Angela
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Cardiovasc Med, S-17176 Stockholm, Sweden..
    St Pourcain, Beate
    Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England.;Max Planck Inst Psycholinguist, NL-6525 XD Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 AJ Nijmegen, Netherlands..
    Timpson, Nicholas J.
    Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Trollor, Julian
    Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW 2052, Australia.;Univ New South Wales, Sch Psychiat, Dept Dev Disabil Neuropsychiat, Sydney, NSW 2031, Australia..
    van Dongen, Jenny
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Amsterdam Univ Med Ctr, Amsterdam Publ Hlth Res Inst, NL-1105 AZ Amsterdam, Netherlands..
    Van Heemst, Diana
    Baylor Coll Med, Houston, TX 77030 USA..
    Visvikis-Siest, Sophie
    Univ Lorraine, IGE PCV, INSERM, F-54000 Nancy, France..
    Vollenweider, Peter
    Lausanne Univ Hosp CHUV, Dept Internal Med, CH-1011 Lausanne, Switzerland.;Univ Lausanne, CH-1011 Lausanne, Switzerland..
    Volker, Uwe
    Univ Turku, MediCity Res Lab, Turku 20520, Finland..
    Waldenberger, Melanie
    Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany..
    Willemsen, Gonneke
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Amsterdam Univ Med Ctr, Amsterdam Publ Hlth Res Inst, NL-1105 AZ Amsterdam, Netherlands..
    Zabaneh, Delilah
    UCL, Dept Genet, Genet Inst, London WC1E 6BT, England..
    Morris, Richard W.
    Univ Bristol, Bristol Med Sch, Dept Populat Hlth Sci, Bristol BS8 1UD, Avon, England..
    Arnett, Donna K.
    Univ Kentucky, Coll Publ Hlth, Deans Off, Lexington, KY 40536 USA..
    Baune, Bernhard T.
    Univ Melbourne, Melbourne Med Sch, Dept Psychiat, Parkville, Vic 3000, Australia.;Univ Munster, Dept Psychiat & Psychotherapy, D-48149 Munster, Germany.;Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic 3000, Australia..
    Boomsma, Dorret, I
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Amsterdam Univ Med Ctr, Amsterdam Publ Hlth Res Inst, NL-1105 AZ Amsterdam, Netherlands..
    Chang, Yen-Pei C.
    Univ Maryland, Dept Med, Sch Med, Baltimore, MD 21202 USA..
    Deary, Ian J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Deloukas, Panos
    Queen Mary Univ London, Barts & London Med Sch, William Harvey Res Inst, London EC1M 6BQ, England.;Queen Mary Univ London, Ctr Genom Hlth, London EC1M 6BQ, England..
    Eriksson, Johan G.
    Univ Helsinki, Natl Inst Hlth & Welf, Helsinki 00014, Finland.;Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki 00014, Finland..
    Evans, David M.
    Univ Queensland, Univ Queensland Diamantina Inst, Woolloongabba, Qld 4102, Australia.;Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Ferreira, Manuel A.
    QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia..
    Gaunt, Tom
    Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS6 2BN, Avon, England.;Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol BS8 2BN, Avon, England..
    Gudnason, Vilmundur
    Iceland Heart Assoc, IS-201 Kopavogur, Iceland.;Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland..
    Hamsten, Anders
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Cardiovasc Med, S-17176 Stockholm, Sweden..
    Heinrich, Joachim
    Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Inst & Clin Occupat Social & Environm Med, Univ Hosp, D-81377 Munich, Germany.;Univ Melbourne, Melbourne Sch Populat & Global Hlth, Allergy & Lung Hlth Unit, Melbourne, Vic 3010, Australia..
    Hingorani, Aroon
    UCL, Inst Cardiovasc Sci, London WC1E 6BT, England..
    Humphries, Steve E.
    UCL, Inst Cardiovasc Sci, London WC1E 6BT, England..
    Jukema, J. Wouter
    Leiden Univ Med Ctr, Dept Internal Med, Sect Gerontol & Geriatr, NL-2333 ZA Leiden, Netherlands.;Durrer Ctr Cardiogenet Res, NL-1105 AZ Amsterdam, Netherlands..
    Koenig, Wolfgang
    Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80636 Munich, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, D-80336 Munich, Germany.;Univ Ulm, Inst Epidemiol & Med Biometry, D-89081 Ulm, Germany..
    Kumari, Meena
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London WC1E 7HB, England.;Univ Essex, Inst Social & Econ Res, Colchester CO4 3SQ, Essex, England..
    Kutalik, Zoltan
    SIB Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland.;Univ Lausanne, Univ Ctr Primary Care & Publ Hlth, CH-1010 Lausanne, Switzerland..
    Lawlor, Deborah A.
    Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS6 2BN, Avon, England.;Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol BS8 2BN, Avon, England..
    Lehtimaki, Terho
    Tampere Univ, Fac Med & Hlth Technol, Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Tampere Univ, Fac Med & Hlth Technol, Finnish Cardiovasc Res Ctr Tampere, Tampere 33520, Finland..
    Marz, Winfried
    Heidelberg Univ, Med Fac Mannheim, Dept Med Nephrol Hypertensiol Rheumatol Endocrino, D-68167 Mannheim, Germany.;Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, A-8036 Graz, Austria.;SYNALB Holding Deutschland GmbH, SYNLAB Acad, D-68163 Mannheim, Germany..
    Mather, Karen A.
    Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW 2052, Australia.;Neurosci Res Australia, Sydney, NSW 2031, Australia..
    Naitza, Silvia
    CNR, Ist Ric Genet & Biomed, I-09042 Monserrato, CA, Italy..
    Nauck, Matthias
    Univ Med Greifswald, Inst Clin Chem & Lab Med, D-17475 Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, D-17475 Greifswald, Germany..
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res CBAR, Dept Internal Med & Clin Nutr, S-41345 Gothenburg, Sweden..
    Price, Jackie F.
    Univ Edinburgh, Usher Inst, Edinburgh EH8 9AG, Midlothian, Scotland..
    Raitakari, Olli
    Univ Turku, Turku Univ Hosp, Ctr Populat Hlth Res, Turku 20520, Finland.;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku 20520, Finland.;Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20014, Finland..
    Rice, Ken
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Sachdev, Perminder S.
    Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW 2052, Australia.;Prince Wales Hosp, Neuropsychiat Inst, Sydney, NSW 2031, Australia..
    Slagboom, Eline
    Leiden Univ Med Ctr, Dept Biomed Data Sci, Sect Mol Epidemiol, NL-2300 RC Leiden, Netherlands.;Max Planck Inst Biol Ageing, D-50931 Cologne, Germany..
    Sorensen, Thorkild I. A.
    Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Sect Metab Genet, DK-2200 Copenhagen, Denmark.;Univ Copenhagen, Dept Publ Hlth, Sect Epidemiol, DK-1014 Copenhagen, Denmark..
    Spector, Tim
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England..
    Stacey, David
    Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge CB1 8RN, England..
    Stathopoulou, Maria G.
    Univ Lorraine, IGE PCV, INSERM, F-54000 Nancy, France..
    Tanaka, Toshiko
    NIA, Translat Gerontol Branch, Longitudinal Study Sect, Baltimore, MD 21224 USA..
    Wannamethee, S. Goya
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Primary Care & Populat Hlth, London NW3 2PF, England..
    Whincup, Peter
    St Georges Univ London, Populat Hlth Res Inst, London SW17 0RE, England..
    Rotter, Jerome, I
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Dept Pediat, Lundquist Inst, Torrance, CA 90502 USA..
    Dehghan, Abbas
    Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX 77030 USA.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA..
    Psaty, Bruce M.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA.;Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA.;Univ Washington, Dept Hlth Serv, Seattle, WA 98101 USA..
    Snieder, Harold
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands..
    Alizadeh, Behrooz Z.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands..
    Genome-wide association study of circulating interleukin 6 levels identifies novel loci2021Ingår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 30, nr 5, s. 393-409Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67428 (n(discovery)=52654 and n(replication)=14774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (P-combined=1.8x10(-11)), HLA-DRB1/DRB5 rs660895 on Chr6p21 (P-combined=1.5x10(-10)) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (P-combined=1.2x10(-122)). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

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  • 12.
    Ahmad, Shafqat
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Harvard Med Sch, Prevent Med Div, Brigham & Womens Hosp, Boston, MA 02115 USA;Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.
    Fatima, Syeda Sadia
    Aga Khan Univ, Dept Biol & Biomed Sci, Karachi, Pakistan.
    Rukh, Gull
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Smith, Caren E.
    Tufts Univ, Res Ctr Aging, Jean Mayer US Dept Agr, Nutr & Genom Lab, Boston, MA 02111 USA.
    Gene Lifestyle Interactions With Relation to Obesity, Cardiometabolic, and Cardiovascular Traits Among South Asians2019Ingår i: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 10, artikel-id 221Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The rapid rise of obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) during the last few decades among South Asians has been largely attributed to a major shift in lifestyles including physical inactivity, unhealthy dietary patterns, and an overall pattern of sedentary lifestyle. Genetic predisposition to these cardiometabolic risk factors may have interacted with these obesogenic environments in determining the higher cardiometabolic disease prevalence. Based on the premise that gene-environment interactions cause obesity and cardiometabolic diseases, we systematically searched the literature and considered the knowledge gaps that future studies might ful fill. We identified only seven published studies that focused specifically on gene-environment interactions for cardiometabolic traits in South Asians, most of which were limited by relatively small sample and lack of replication. Some studies reported that the differences in metabolic response to higher physical activity and low caloric diet might be modified by genetic risk related to these cardiometabolic traits. Although studies on gene lifestyle interactions in cardiometabolic traits report significant interactions, future studies must focus on more precise assessment of lifestyle factors, investigation of a larger set of genetic variants and the application of powerful statistical methods to facilitate translatable approaches. Future studies should also be integrated with findings both using mechanistic studies through laboratory settings and randomized clinical trials for clinical outcomes.

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    FULLTEXT01
  • 13.
    Akram, Talia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE-C)-PIEAS, Faisalabad, Pakistan.
    Fatima, Ambrin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Klar, Joakim
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Hoeber, Jan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Zakaria, Muhammad
    Tariq, Muhammad
    Baig, Shahid M.
    Schuster, Jens
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Dahl, Niklas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Aberrant splicing due to a novel RPS7 variant causes Diamond-Blackfan Anemia associated with spontaneous remission and meningocele2020Ingår i: International Journal of Hematology, ISSN 0925-5710, E-ISSN 1865-3774, Vol. 112, nr 6, s. 894-899Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Diamond-Blackfan Anemia (DBA) is a congenital pure red cell aplasia caused by heterozygous variants in ribosomal protein genes. The hematological features associated with DBA are highly variable and non-hematological abnormalities are common. We report herein on an affected mother and her daughter presenting with transfusion-dependent anemia. The mother showed mild physical abnormalities and entered spontaneous remission at age 13 years. Her daughter was born with occipital meningocele. Exome sequencing of DNA from the mother revealed a heterozygous novel splice site variant (NM_001011.4:c.508-3T > G) in the Ribosomal Protein S7 gene (RPS7) inherited by the daughter. Functional analysis of the RPS7 variant expressed from a mini-gene construct revealed that the exon 7 acceptor splice site was replaced by a cryptic splice resulting in a transcript missing 64 bp of exon 7 (p.Val170Serfs*8). Our study confirms a pathogenic effect of a novel RPS7 variant in DBA associated with spontaneous remission in the mother and meningocele in her daughter, thus adding to the genotype-phenotype correlations in DBA.

  • 14.
    Alemi, Mansour
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Molecular biological techniques as a tool in diagnostic pathology: Applications in B-cell lymphoproliferative disease, medullary thyroid carcinoma and cervical carcinoma2000Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Identification of malignancy associated with mutations in gene sequences requires detection ofas little as a single base difference. A powerful technique in mutation detection is polymerasechain reaction (PCR) followed by single-strand conformational polymorphism (SSCP) andsequencing.

    The present investigation is focused on improving tests for the following diagnostic questions:(i) clonality in malignancy of lymphoid origin by developing simple laboratory methodsbased on PCR in which the monoclonal B-cell lineage can be distinguished from thepolyclonal, (ii) presence of mutations in RET proto-oncogene involved in sporadic medullarythyroid carcinoma (MTC), and (iii) development of a simple test which can distinguishbetween prototype human papillomavirus 16 (HPV16) and variant HPV16 containing a pointmutation at codon 83 of the E6 gene.

    The rearrangement of the immunoglobulin heavy chain gene can be used as a marker of B-celllineage and clonality. By using PCR with specific primers corresponding to the variable and joining regions, it is possible to detect the rearrangement of a small amount of clonal B-cells ina polyclonal background. This study has shown that the SSCP analysis of PCR fragmentsincreases the sensitivity and the specificity of the test.

    Oncogenic activation of the RET related to somatic missense mutations has been shown insporadic MTC. These mutations are believed to play an important role in the tumorigenesis ofMTC. By combining microdissection of tumor cells followed by PCR-SSCP, fragment sizeanalysis and sequencing, a small proportion of cells with mutation in a subpopulation of cellswithin a tumor can be detected. A variant of HPV 16 has previously been shown to be moreprevalent in invasive cervical carcinoma than in preinvasive lesions. In the present study asimple, rapid PCR-SSCP assay has been developed to identify women who are at increasedrisk of progression to invasive cervical carcinoma.

  • 15.
    Algady, Walid
    et al.
    Univ Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, England.
    Louzada, Sandra
    Wellcome Sanger Inst, Cambridge CB10 1SA, England.
    Carpenter, Danielle
    Univ Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, England.
    Brajer, Paulina
    Univ Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, England.
    Farnert, Anna
    Karolinska Inst, Dept Med Solna, Div Infect Dis, S-17176 Stockholm, Sweden;Karolinska Univ Hosp, Dept Infect Dis, S-17176 Stockholm, Sweden.
    Rooth, Ingegerd
    Natl Inst Med Res, Nyamisati Malaria Res, Dar Es Salaam, Tanzania.
    Ngasala, Billy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH), Internationell barnhälsa och nutrition. Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania.
    Yang, Fengtang
    Wellcome Sanger Inst, Cambridge CB10 1SA, England.
    Shaw, Marie-Anne
    Univ Leeds, Leeds Inst Med Res St Jamess, Leeds LS9 7TF, W Yorkshire, England.
    Hollox, Edward J.
    Univ Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, England.
    The Malaria-Protective Human Glycophorin Structural Variant DUP4 Shows Somatic Mosaicism and Association with Hemoglobin Levels2018Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 103, nr 5, s. 769-776Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glycophorin A and glycophorin B are red blood cell surface proteins and are both receptors for the parasite Plasmodium falciparum, which is the principal cause of malaria in sub-Saharan Africa. DUP4 is a complex structural genomic variant that carries extra copies of a glycophorin A-glycophorin B fusion gene and has a dramatic effect on malaria risk by reducing the risk of severe malaria by up to 40%. Using fiber-FISH and Illumina sequencing, we validate the structural arrangement of the glycophorin locus in the DUP4 variant and reveal somatic variation in copy number of the glycophorin B-glycophorin A fusion gene. By developing a simple, specific, PCR-based assay for DUP4, we show that the DUP4 variant reaches a frequency of 13% in the population of a malaria-endemic village in southeastern Tanzania. We genotype a substantial proportion of that village and demonstrate an association of DUP4 genotype with hemoglobin levels, a phenotype related to malaria, using a family-based association test. Taken together, we show that DUP4 is a complex structural variant that may be susceptible to somatic variation and show that DUP4 is associated with a malarial-related phenotype in a longitudinally followed population.

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  • 16.
    Alhaidan, Yazeid
    et al.
    Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark.;Univ Southern Denmark, Fac Hlth Sci, Dept Clin Res, DK-5000 Odense C, Denmark.;King Abdullah Int Med Res Ctr, Dept Med Genom Res, Riyadh 11426, Saudi Arabia.;King Saud Bin Abdulaziz Univ Hlth Sci, Riyadh, Saudi Arabia..
    Larsen, Martin J.
    Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark.;Univ Southern Denmark, Fac Hlth Sci, Dept Clin Res, DK-5000 Odense C, Denmark..
    Schou, Anders Jorgen
    Odense Univ Hosp, Hans Christian Andersen Childrens Hosp, DK-5000 Odense C, Denmark..
    Stenlid, Maria H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Al Balwi, Mohammed A.
    King Abdullah Int Med Res Ctr, Dept Med Genom Res, Riyadh 11426, Saudi Arabia.;King Saud Bin Abdulaziz Univ Hlth Sci, Riyadh, Saudi Arabia..
    Christesen, Henrik Thybo
    Univ Southern Denmark, Fac Hlth Sci, Dept Clin Res, DK-5000 Odense C, Denmark.;Odense Pancreases Ctr, Www OPA Cnu, Uppsala, Sweden..
    Brusgaard, Klaus
    Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark.;Univ Southern Denmark, Fac Hlth Sci, Dept Clin Res, DK-5000 Odense C, Denmark.;Near East Univ, Nicosia, Cyprus..
    Exome sequencing revealed DNA variants in NCOR1, IGF2BP1, SGLT2 and NEK11 as potential novel causes of ketotic hypoglycemia in children2020Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 10, nr 1, artikel-id 2114Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Unexplained or idiopathic ketotic hypoglycemia (KH) is the most common type of hypoglycemia in children. The diagnosis is based on the exclusion of routine hormonal and metabolic causes of hypoglycemia. We aimed to identify novel genes that cause KH, as this may lead to a more targeted treatment. Deep phenotyping of ten preschool age at onset KH patients (boys, n = 5; girls, n = 5) was performed followed by trio exome sequencing and comprehensive bioinformatics analysis. Data analysis revealed four novel candidate genes: (1) NCOR1 in a patient with KH, iron deficiency and loose stools; (2) IGF2BP1 in a proband with KH, short stature and delayed bone age; (3) SLC5A2 in a proband with KH, intermittent glucosuria and extremely elevated p-GLP-1; and (4) NEK11 in a proband with ketotic hypoglycemia and liver affliction. These genes are associated with different metabolic processes, such as gluconeogenesis, translational regulation, and glucose transport. In conclusion, WES identified DNA variants in four different genes as potential novel causes of IKH, suggesting that IKH is a heterogeneous disorder that can be split into several novel diseases: NCOR1-KH, IGF2BP1-KH, SGLT2-KH or familial renal glucosuria KH, and NEK11-KH. Precision medicine treatment based on exome sequencing may lead to advances in the management of IKH.

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  • 17.
    Ali, Muhammad Akhtar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Understanding Cancer Mutations by Genome Editing2014Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Mutational analyses of cancer genomes have identified novel candidate cancer genes with hitherto unknown function in cancer. To enable phenotyping of mutations in such genes, we have developed a scalable technology for gene knock-in and knock-out in human somatic cells based on recombination-mediated construct generation and a computational tool to design gene targeting constructs. Using this technology, we have generated somatic cell knock-outs of the putative cancer genes ZBED6 and DIP2C in human colorectal cancer cells. In ZBED6-/- cells complete loss of functional ZBED6 was validated and loss of ZBED6 induced the expression of IGF2. Whole transcriptome and ChIP-seq analyses revealed relative enrichment of ZBED6 binding sites at upregulated genes as compared to downregulated genes. The functional annotation of differentially expressed genes revealed enrichment of genes related to cell cycle and cell proliferation and the transcriptional modulator ZBED6 affected the cell growth and cell cycle of human colorectal cancer cells. In DIP2C-/-cells, transcriptome sequencing revealed 780 differentially expressed genes as compared to their parental cells including the tumour suppressor gene CDKN2A. The DIP2C regulated genes belonged to several cancer related processes such as angiogenesis, cell structure and motility. The DIP2C-/-cells were enlarged and grew slower than their parental cells. To be able to directly compare the phenotypes of mutant KRAS and BRAF in colorectal cancers, we have introduced a KRASG13D allele in RKO BRAFV600E/-/-/ cells. The expression of the mutant KRAS allele was confirmed and anchorage independent growth was restored in KRASG13D cells. The differentially expressed genes both in BRAF and KRAS mutant cells included ERBB, TGFB and histone modification pathways. Together, the isogenic model systems presented here can provide insights to known and novel cancer pathways and can be used for drug discovery.

    Delarbeten
    1. Computational and molecular tools for scalable rAAV mediated genome editing
    Öppna denna publikation i ny flik eller fönster >>Computational and molecular tools for scalable rAAV mediated genome editing
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The rapid discovery of potential driver mutations through large scale mutational analyses of human cancers generates a need to characterize their cellular phenotypes. Among the techniques for genome editing, recombinant adeno-associated virus (rAAV) mediated gene targeting is particularly suited to knock-in of single nucleotide substitutions. However, the generation of gene targeting constructs and the targeting process is time consuming and labor-intense. To facilitate rAAV mediated gene targeting, we developed the first software and complementary automation friendly vector tools to generate optimized targeting constructs for editing human protein encoding genes. By computational approaches, rAAV constructs for editing ~72% of bases in protein-coding exons were designed. Similarly, ~81% of genes were predicted to be targetable by rAAV mediated knock-out. A Gateway based cloning system for facile generation of rAAV constructs suitable for robotic automation was developed and used in successful generation of targeting constructs. Together, these tools enable automated rAAV targeting construct design, generation as well as enrichment and expansion of targeted cells with desired integrations.

    Nationell ämneskategori
    Medicinsk genetik
    Identifikatorer
    urn:nbn:se:uu:diva-235563 (URN)
    Tillgänglig från: 2014-11-05 Skapad: 2014-11-05 Senast uppdaterad: 2018-01-11
    2. The transcriptional modulator ZBED6 regulates cell cycle and growth of human colorectal cancer cells
    Öppna denna publikation i ny flik eller fönster >>The transcriptional modulator ZBED6 regulates cell cycle and growth of human colorectal cancer cells
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The transcription factor ZBED6 is a repressor of IGF2 whose action impacts development, cell proliferation and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Transcriptome analyses revealed enrichment of cell cycle-related processes among differentially expressed genes in both cell lines. Chromatin immunoprecipitation sequencing analyses displayed enrichment of ZBED6 binding at genes upregulated in ZBED6-/- knockout clones. Ten differentially expressed genes were identified as putative direct gene targets and their downregulation by ZBED6 was experimentally validated. Eight of these genes were linked to the Wnt, Hippo, TGF-b, EGFR or PI3K pathways, all involved in colorectal cancer development. Ablation of ZBED6 affected the cell cycle and led to increased growth rate of ZBED6-/- RKO cells. These observations support a role for transcriptional modulation by ZBED6 in cell cycle regulation and growth of colorectal cancers.

    Nationell ämneskategori
    Medicinsk genetik
    Identifikatorer
    urn:nbn:se:uu:diva-235564 (URN)
    Tillgänglig från: 2014-11-05 Skapad: 2014-11-05 Senast uppdaterad: 2018-01-11
    3. DIP2C regulates expression of the tumor suppressor gene CDKN2A
    Öppna denna publikation i ny flik eller fönster >>DIP2C regulates expression of the tumor suppressor gene CDKN2A
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The disco-interacting protein 2 homolog C (DIP2C) gene is an uncharacterized candidate

    breast and lung cancer gene. The gene contains a DMAP1 binding domain, pointing to

    potential involvement in DNMT1-dependent methylation. To study the role of DIP2C in

    tumor development, we engineered human DIP2C knockout cell systems by rAAV-mediated

    gene targeting. Homo- and heterozygous RKO DIP2C knockout cells displayed enlarged cells

    and growth retardation. This phenotype was most pronounced in DIP2C-/- knockouts, and

    these cells also displayed a significant decrease in DIP2C mRNA levels. RNA sequencing

    revealed 780 genes affected by the loss of DIP2C, including the cellular senescence marker

    P16INK4a. Functional annotation of the regulated genes shows enrichment of genes involved

    with cell death processes, cell structure and motility. Furthermore, KEGG pathway analysis

    shows association of 19 genes with pathways in cancer. In conclusion, the phenotypic data

    and expression changes induced by loss of DIP2C indicate that the gene function may be

    important for several biological processes implicated in cancer, and that loss of gene function

    may be a trigger of cellular senescence.

    Nationell ämneskategori
    Medicinsk genetik
    Identifikatorer
    urn:nbn:se:uu:diva-235565 (URN)
    Tillgänglig från: 2014-11-05 Skapad: 2014-11-05 Senast uppdaterad: 2018-01-11
    4. Core Ras Pathway Signaling in Human Colorectal Cancers Revealed by Isogenic Modeling of NF1, KRAS and BRAF Mutations
    Öppna denna publikation i ny flik eller fönster >>Core Ras Pathway Signaling in Human Colorectal Cancers Revealed by Isogenic Modeling of NF1, KRAS and BRAF Mutations
    2012 (Engelska)Ingår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 48, nr Suppl.5, s. S118-S118Artikel i tidskrift, Meeting abstract (Refereegranskat) Published
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-194476 (URN)10.1016/S0959-8049(12)71162-0 (DOI)000313036501006 ()
    Konferens
    22nd Biennial Congress of the European-Association-for-Cancer-Research, JUL 07-10, 2012, Barcelona, SPAIN
    Tillgänglig från: 2013-02-15 Skapad: 2013-02-14 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
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  • 18.
    Ali, Muhammad Akhtar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Younis, Shady
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Wallerman, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Gupta, Rajesh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Andersson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Tobias Sjöblom, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    The transcriptional modulator ZBED6 regulates cell cycle and growth of human colorectal cancer cellsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The transcription factor ZBED6 is a repressor of IGF2 whose action impacts development, cell proliferation and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Transcriptome analyses revealed enrichment of cell cycle-related processes among differentially expressed genes in both cell lines. Chromatin immunoprecipitation sequencing analyses displayed enrichment of ZBED6 binding at genes upregulated in ZBED6-/- knockout clones. Ten differentially expressed genes were identified as putative direct gene targets and their downregulation by ZBED6 was experimentally validated. Eight of these genes were linked to the Wnt, Hippo, TGF-b, EGFR or PI3K pathways, all involved in colorectal cancer development. Ablation of ZBED6 affected the cell cycle and led to increased growth rate of ZBED6-/- RKO cells. These observations support a role for transcriptional modulation by ZBED6 in cell cycle regulation and growth of colorectal cancers.

  • 19.
    Ali, Zafar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Zulfiqar, Shumaila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Klar, Joakim
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Wikström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Ullah, Farid
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Khan, Ayaz
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Abdullah, Uzma
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Baig, Shahid
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Dahl, Niklas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Homozygous GRID2 missense mutation predicts a shift in the D-serine binding domain of GluD2 in a case with generalized brain atrophy and unusual clinical features2017Ingår i: BMC Medical Genetics, E-ISSN 1471-2350, Vol. 18, nr 1, artikel-id 144Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Spinocerebellar ataxias comprise a large and heterogeneous group of disorders that may present with isolated ataxia, or ataxia in combination with other neurologic or non-neurologic symptoms. Monoallelic or biallelic GRID2 mutations were recently reported in rare cases with cerebellar syndrome and variable degree of ataxia, ocular symptoms, hypotonia and developmental delay.

    CASE PRESENTATION: We report on a consanguineous family with autosomal recessive childhood onset of slowly progressive cerebellar ataxia and delayed psychomotor development in three siblings. MRI of an adult and affected family member revealed slightly widened cerebral and cerebellar sulci, suggesting generalized brain atrophy, and mild cerebellar atrophy. Using whole exome sequencing we identified a novel homozygous missense variant [c.2128C > T, p.(Arg710Trp)] in GRID2 that segregates with the disease. The missense variant is located in a conserved region encoding the extracellular serine-binding domain of the GluD2 protein and predicts a change in conformation of the protein.

    CONCLUSION: The widespread supratentorial brain abnormalities, absence of oculomotor symptoms, increased peripheral muscle tone and the novel missense mutation add to the clinical and genetic variability in GRID2 associated cerebellar syndrome. The neuroradiological findings in our family indicate a generalized neurodegenerative process to be taken into account in other families segregating complex clinical features and GRID2 mutations.

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  • 20. Allara, Elias
    et al.
    Lee, Wei-Hsuan
    Burgess, Stephen
    Larsson, Susanna C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Medicinsk epidemiologi. Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Genetically predicted cortisol levels and risk of venous thromboembolism2022Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 17, nr 8, artikel-id e0272807Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION: In observational studies, venous thromboembolism (VTE) has been associated with Cushing's syndrome and with persistent mental stress, two conditions associated with higher cortisol levels. However, it remains unknown whether high cortisol levels within the usual range are causally associated with VTE risk. We aimed to assess the association between plasma cortisol levels and VTE risk using Mendelian randomization.

    METHODS: Three genetic variants in the SERPINA1/SERPINA6 locus (rs12589136, rs11621961 and rs2749527) were used to proxy plasma cortisol. The associations of the cortisol-associated genetic variants with VTE were acquired from the INVENT (28 907 cases and 157 243 non-cases) and FinnGen (6913 cases and 169 986 non-cases) consortia. Corresponding data for VTE subtypes were available from the FinnGen consortium and UK Biobank. Two-sample Mendelian randomization analyses (inverse-variance weighted method) were performed.

    RESULTS: Genetic predisposition to higher plasma cortisol levels was associated with a reduced risk of VTE (odds ratio [OR] per one standard deviation increment 0.73, 95% confidence interval [CI] 0.62-0.87, p<0.001). The association was stronger for deep vein thrombosis (OR 0.69, 95% CI 0.55-0.88, p = 0.003) than for pulmonary embolism which did not achieve statistical significance (OR 0.83, 95% CI 0.63-1.09, p = 0.184). Adjusting for genetically predicted systolic blood pressure inverted the direction of the point estimate for VTE, although the resulting CI was wide (OR 1.06, 95% CI 0.70-1.61, p = 0.780).

    CONCLUSIONS: This study provides evidence that genetically predicted plasma cortisol levels in the high end of the normal range are associated with a decreased risk of VTE and that this association may be mediated by blood pressure. This study has implications for the planning of observational studies of cortisol and VTE, suggesting that blood pressure traits should be measured and accounted for.

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  • 21.
    Allum, Fiona
    et al.
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Hedman, Asa K.
    Karolinska Inst, Cardiovasc Med Unit, Dept Med Solna, S-17176 Stockholm, Sweden.
    Shaol, Xiaojian
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Cheung, Warren A.
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada;Childrens Mercy Hosp & Clin, Kansas City, MO 64108 USA.
    Vijay, Jinchu
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Guenard, Frederic
    Univ Laval, Inst Nutr & Funct Foods INAF, Quebec City, PQ G1V 0A6, Canada.
    Kwan, Tony
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Simon, Marie-Michelle
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Ge, Bing
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Moura, Cristiano
    McGill Univ, Dept Epidemiol, Montreal, PQ H3A 1A2, Canada.
    Boulier, Elodie
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Bernatsky, Sasha
    McGill Univ, Dept Epidemiol, Montreal, PQ H3A 1A2, Canada.
    Lathropl, Mark
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    McCarthy, Mark, I
    Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Old Rd, Oxford OX3 7LJ, England;Univ Oxford, Wellcome Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England;Oxford Univ Hosp NHS Fdn Trust, John Radcliffe Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 9DU, England.
    Deloukas, Panos
    Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, Charterhouse Sq, London EC1M 6BQ, England.
    Tchernof, Andre
    Univ Laval, Quebec Heart & Lung Inst, Quebec City, PQ G1V 0A6, Canada.
    Pastinen, Tomi
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada;Childrens Mercy Hosp & Clin, Kansas City, MO 64108 USA.
    Vohl, Marie-Claude
    Univ Laval, Inst Nutr & Funct Foods INAF, Quebec City, PQ G1V 0A6, Canada.
    Grundberg, Elin
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada;Childrens Mercy Hosp & Clin, Kansas City, MO 64108 USA.
    Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements2019Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 10, artikel-id 1209Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sparse profiling of CpG methylation in blood by microarrays has identified epigenetic links to common diseases. Here we apply methylC-capture sequencing (MCC-Seq) in a clinical population of similar to 200 adipose tissue and matched blood samples (N-total similar to 400), providing high- resolution methylation profiling (>1.3 M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in similar to 800 independent adipose tissue and blood samples from the general population. We follow-up on adipose-specific regulatory regions under (1) genetic and (2) epigenetic (environmental) regulation via integrational studies. Overall, the comprehensive sequencing of regulatory element methylomes reveals a rich landscape of functional variants linked genetically as well as epigenetically to plasma lipid traits.

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    FULLTEXT01
  • 22.
    Almkvist, Ove
    et al.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, SE-14157 Stockholm, Sweden.
    Rodriguez-Vieitez, Elena
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, SE-14157 Stockholm, Sweden.
    Thordardottir, Steinunn
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Stockholm, Sweden.
    Nordberg, Agneta
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, SE-14157 Stockholm, Sweden.
    Viitanen, Matti
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, SE-14157 Stockholm, Sweden.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Graff, Caroline
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Stockholm, Sweden.
    Longitudinal cognitive decline in autosomal-dominant Alzheimer's disease varies with mutations in APP and PSEN1 genes2019Ingår i: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 82, s. 40-47Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The purpose was to compare longitudinal cognitive changes in APP and PSEN1 gene mutation carriers and noncarriers from four autosomal-dominant Alzheimer's disease (ADAD) families across preclinical and early clinical stages of disease. Carriers (n = 34) with four different mutations (PSEN1(M146V), PSEN1(H163Y), APP(SWE), and APP(ARC)) and noncarriers (n = 41) were followed up longitudinally with repeated cognitive assessments starting many years before the expected clinical onset. The relationship between cognition and years to expected clinical onset, education, age, and type of mutation was analyzed using mixed-effects models. Results showed an education-dependent and time-related cognitive decline with linear and quadratic predictors in mutation carriers. Cognitive decline began close to the expected clinical onset and was relatively rapid afterward in PSEN1 mutation carriers, whereas decline was slower and started earlier than 10 years before expected clinical onset in APP mutation carriers. In noncarriers, the decline was minimal across time in accordance with normal aging. These results suggest that phenotypes for onset and rate of cognitive decline vary with PSEN1 and APP genes, suggesting a behavioral heterogeneity in ADAD. (C) 2019 Elsevier Inc. All rights reserved.

  • 23.
    Almén, Markus Sällman
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Nilsson, Emil K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Jacobsson, Josefin A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Kalnina, Ineta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Klovins, Janis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Fredriksson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Genome-wide analysis reveals DNA methylation markers that vary with both age and obesity2014Ingår i: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 548, nr 1, s. 61-67Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The combination of the obesity epidemic and an aging population presents growing challenges for the healthcare system. Obesity and aging are major risk factors for a diverse number of diseases and it is of importance to understand their interaction and the underlying molecular mechanisms. Herein the authors examined the methylation levels of 27578 CpG sites in 46 samples from adult peripheral blood. The effect of obesity and aging was ascertained with general linear models. More than one hundred probes were correlated to aging, nine of which belonged to the KEGG group map04080. Additionally, 10 CpG sites had diverse methylation profiles in obese and lean individuals, one of which was the telomerase catalytic subunit (TERT). In eight of ten cases the methylation change was reverted between obese and lean individuals. One region proved to be differentially methylated with obesity (LINC00304) independent of age. This study provides evidence that obesity influences age driven epigenetic changes, which provides a molecular link between aging and obesity. This link and the identified markers may prove to be valuable biomarkers for the understanding of the molecular basis of aging, obesity and associated diseases.

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  • 24.
    Ameur, Adam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    CRISPR and Long-Read Sequencing: A Perfect Match.2020Ingår i: The CRISPR journal, ISSN 2573-1602, Vol. 3, nr 6, s. 425-427, artikel-id spec.issueArtikel i tidskrift (Refereegranskat)
  • 25.
    Ameur, Adam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Bunikis, Ignas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    CanvasDB: a local database infrastructure for analysis of targeted- and whole genome re-sequencing projects2014Ingår i: Database: The Journal of Biological Databases and Curation, E-ISSN 1758-0463, s. bau098-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    CanvasDB is an infrastructure for management and analysis of genetic variants from massively parallel sequencing (MPS) projects. The system stores SNP and indel calls in a local database, designed to handle very large datasets, to allow for rapid analysis using simple commands in R. Functional annotations are included in the system, making it suitable for direct identification of disease-causing mutations in human exome-(WES) or whole-genome sequencing (WGS) projects. The system has a built-in filtering function implemented to simultaneously take into account variant calls from all individual samples. This enables advanced comparative analysis of variant distribution between groups of samples, including detection of candidate causative mutations within family structures and genome-wide association by sequencing. In most cases, these analyses are executed within just a matter of seconds, even when there are several hundreds of samples and millions of variants in the database. We demonstrate the scalability of canvasDB by importing the individual variant calls from all 1092 individuals present in the 1000 Genomes Project into the system, over 4.4 billion SNPs and indels in total. Our results show that canvasDB makes it possible to perform advanced analyses of large-scale WGS projects on a local server.

  • 26.
    Anande, Govardhan
    et al.
    Univ New South Wales Sydney, Adult Canc Program, Lowy Canc Res Ctr, Sydney, NSW, Australia.;Univ New South Wales Sydney, Prince Wales Clin Sch, Sydney, NSW, Australia..
    Deshpande, Nandan P.
    Univ New South Wales Sydney, Sch Biotechnol & Biomol Sci, Sydney, NSW, Australia..
    Mareschal, Sylvain
    Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Batcha, Aarif M. N.
    Ludwig Maximilians Univ Munchen, Fac Med, Inst Med Data Proc Biometr & Epidemiol, Munich, Germany.;Ludwig Maximilians Univ Munchen, Data Integrat Future Med, Munich, Germany..
    Hampton, Henry R.
    Univ New South Wales Sydney, Adult Canc Program, Lowy Canc Res Ctr, Sydney, NSW, Australia.;Univ New South Wales Sydney, Prince Wales Clin Sch, Sydney, NSW, Australia..
    Herold, Tobias
    Ludwig Maximilians Univ Munchen, Univ Hosp, Dept Med 3, Munich, Germany.;Helmholtz Zentrum Munchen, Res Unit Apoptosis Hematopoiet Stem Cells, German Res Ctr Environm Hlth, Munich, Germany..
    Lehmann, Sören
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi. Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Wilkins, Marc R.
    Univ New South Wales Sydney, Sch Biotechnol & Biomol Sci, Sydney, NSW, Australia..
    Wong, Jason W. H.
    Univ New South Wales Sydney, Adult Canc Program, Lowy Canc Res Ctr, Sydney, NSW, Australia.;Univ New South Wales Sydney, Prince Wales Clin Sch, Sydney, NSW, Australia.;Univ Hong Kong, Li Ka Shing Fac Med, Sch Biomed Sci, Hong Kong, Peoples R China..
    Unnikrishnan, Ashwin
    Univ New South Wales Sydney, Adult Canc Program, Lowy Canc Res Ctr, Sydney, NSW, Australia.;Univ New South Wales Sydney, Prince Wales Clin Sch, Sydney, NSW, Australia..
    Pimanda, John E.
    Univ New South Wales Sydney, Adult Canc Program, Lowy Canc Res Ctr, Sydney, NSW, Australia.;Univ New South Wales Sydney, Prince Wales Clin Sch, Sydney, NSW, Australia.;Univ New South Wales Sydney, Sch Med Sci, Dept Pathol, Sydney, NSW, Australia.;Prince Wales Hosp, Dept Haematol, Sydney, NSW, Australia..
    RNA Splicing Alterations Induce a Cellular Stress Response Associated with Poor Prognosis in Acute Myeloid Leukemia2020Ingår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 26, nr 14, s. 3597-3607Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: RNA splicing is a fundamental biological process that generates protein diversity from a finite set of genes. Recurrent somatic mutations of splicing factor genes are common in some hematologic cancers but are relatively uncommon in acute myeloid leukemia (AML, < 20% of patients). We examined whether RNA splicing differences exist in AML, even in the absence of splicing factor mutations.

    Experimental Design: We developed a bioinformatics pipeline to study alternative RNA splicing in RNA-sequencing data from large cohorts of patients with AML.

    Results: We have identified recurrent differential alternative splicing between patients with poor and good prognosis. These splicing events occurred even in patients without any discernible splicing factor mutations. Alternative splicing recurrently occurred in genes with specific molecular functions, primarily related to protein translation. Developing tools to predict the functional impact of alternative splicing on the translated protein, we discovered that approximately 45% of the splicing events directly affected highly conserved protein domains. Several splicing factors were themselves misspliced and the splicing of their target transcripts were altered. Studying differential gene expression in the same patients, we identified that alternative splicing of protein translation genes in ELNAdv patients resulted in the induction of an integrated stress response and upregulation of inflammation-related genes. Finally, using machine learning techniques, we identified a splicing signature of four genes which refine the accuracy of existing risk prognosis schemes and validated it in a completely independent cohort.

    Conclusions: Our discoveries therefore identify aberrant alternative splicing as a molecular feature of adverse AML with clinical relevance.

  • 27.
    Andersson, Ann-Catrin
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Studies on Human Endogenous Retroviruses (HERVs) with Special Focus on ERV32002Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Human endogenous retroviruses (HERVs) represent approximately 7% of the human genome. This investigation was focused on one particular HERV, ERV3, with the main purpose of characterising its gene expression patterns and genomic distribution of ERV3-like sequences. Furthermore, this careful expression study should provide insights into the biological role of HERVs. The impact of HERVs in health and disease is not yet clarified. ERV3 is expressed as three envelope (env) transcripts, of which two also contain a cellular gene, H-plk (human proviral linked Krüppel). ERV3 env expression was mainly investigated at the RNA level. The gene expression of two other HERVs, HERV-K and HERV-E was analysed and compared with ERV3 activity.

    Real-time PCRs were developed and in combination with in situ hybridisation, it was found that ERV3 is expressed in a tissue- and cell-specific way. High levels of ERV3 mRNA (up to six times over Histone3.3) were demonstrated in placenta, sebaceous glands, foetal and adult adrenal glands, brown adipose tissue, corpus luteum, pituitary gland, thymus and testis. In monocytic cells including both normal monocytes and malignant U-937 cells, elevated mRNA levels were observed after retinoic acid (RA)-induced differentiation. ERV3-encoded Env protein was detected in selected cases, one following RA-treatment. In addition, several new ERV3-like sequences were discovered in the human genome.

    ERV3 was found to have conserved open reading frames in contrast to other ERV3-like sequences in the human genome. This suggests that ERV3 may be involved in important cellular processes such as differentiation, cell fusion, immunomodulation and protection against infectious retroviruses. The developed techniques and obtained results will allow further studies of HERV expression to better correlate HERV activity to both normal development and disease.

    Delarbeten
    1. Elevated levels of the human endogenous retrovirus ERV3 in human sebaceous glands
    Öppna denna publikation i ny flik eller fönster >>Elevated levels of the human endogenous retrovirus ERV3 in human sebaceous glands
    Visa övriga...
    1996 (Engelska)Ingår i: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 106, nr 1, s. 125-128Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    ERV3 (HERV-R) is a complete human endogenous retrovirus located on the long arm of chromosome 7. Long terminal repeat-envelope (env) gene spliced mRNAs of 9 and 3.5 kb are widely expressed in human tissues and cells, but gag-pol mRNAs have not been found. Furthermore, the env gp70 gene contains an open reading frame throughout its length. The highest expression of ERV3 mRNA detected so far is in placenta and the lowest in choriocarcinoma cell lines. We have previously shown that the human monoblastic cell line U-937 and some normal and neoplastic tissues also express high levels of ERV3 env message by Northern blot analysis; however, this method does not distinguish between mRNA expression in different cell types in tissues. In this report, we have studied the ERV3 mRNA expression in specific cell types of human skin by in situ hybridization. We found high levels expression of ERV3 env mRNA in human sebaceous glands in normal skin and dermoid cysts of the ovary. In all glands, the expression is maximal in the periphery of the lobule and ceases towards the center in the region of characteristic holocrine secretion. Since it is known that the regulation of sebaceous glands is primarily via steroid hormones, particularly androgens, it is possible that expression of ERV3 is hormone dependent.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-89897 (URN)10.1111/1523-1747.ep12329612 (DOI)8592062 (PubMedID)
    Tillgänglig från: 2002-05-10 Skapad: 2002-05-10 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    2. Expression of the endogenous retrovirus ERV3 (HERV-R) during induced monocytic differentiation in the U-937 cell line
    Öppna denna publikation i ny flik eller fönster >>Expression of the endogenous retrovirus ERV3 (HERV-R) during induced monocytic differentiation in the U-937 cell line
    Visa övriga...
    1996 (Engelska)Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 67, nr 3, s. 451-456Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    ERV3 (HERV-R) is a complete human endogenous retrovirus located on the long arm of chromosome 7. LTR-env-gene-spliced mRNA of 9 and 3.5 Kb is widely expressed in human tissues and cells, but gag-pol mRNA has not been found. Further, the env gp70 gene contains an open reading frame throughout its length and its expression has recently been detected as a full-length protein. The highest expression of ERV3 detected so far is in placenta and the lowest in cytotrophoblasts and choriocarcinoma cell lines. In this report we have studied ERV3 mRNA and protein expression in the human monoblastic cell line U-937 during differentiation into monocytes/macrophages. Differentiation of U-937 cells was induced by 1,25a-dihydroxyvitamin D3 (vitD3), retinoic acid (RA), gamma interferon (IFN-gamma) and phorbol-myristate-acetate (PMA-TPA). The expression of ERV3 env mRNA was found to be differentiation-associated, with high expression detected in the late stages of monocytic development. Using TPA, the expression of ERV3 env was detected as 9- and 3.5-kb transcripts by Northern blotting, as mRNA by in situ hybridization and as a cytoplasmic 65-kDa protein by immunofluorescence and Western blots. Low levels of basal expression were found, with up-regulation of both message and protein at 24 to 48 hr after addition of TPA. Induction with vitD3, IFN-gamma and RA produced higher levels of mRNA at earlier time points. It is concluded that the U-937 cell line represents an excellent model system for further studies to study the relationship between ERV3 expression and cellular differentiation.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-89898 (URN)10.1002/(SICI)1097-0215(19960729)67:3<451::AID-IJC23>3.0.CO;2-9 (DOI)8707424 (PubMedID)
    Tillgänglig från: 2002-05-10 Skapad: 2002-05-10 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    3. Developmnental expression of HERV-R (ERV3) and HERV-K in human tissue
    Öppna denna publikation i ny flik eller fönster >>Developmnental expression of HERV-R (ERV3) and HERV-K in human tissue
    Visa övriga...
    2002 (Engelska)Ingår i: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 297, nr 2, s. 220-225Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The human endogenous retroviruses (HERVs), ERV3 (HERV-R) and HERV-K, are both known to be transcriptionally active in human placenta. In the case of ERV3 there is also indirect evidence for its participation in cellular differentiation. In this study we examined the expression of ERV3 (HERV-R) and HERV-K in human normal fetal tissues by in situ hybridization. The highest level of ERV3 env expression was detected in primitive adrenal cortex. Elevated levels of expression were also found in the following developing tissues: kidneys (tubules), tongue, heart, liver, and central nervous system. Tissue-specific expression was found for HERV-K rec (former cORF) but not for pol/int transcripts. The highest rec expression was found in placenta and levels slightly higher than sense control were found in the rest of the tissues examined. Pol/Int was not possible to quantitate. It appears that ERV3 is expressed in an organ-specific way during embryogenesis and might suggest a possible role in the development and differentiation of human tissues.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-89899 (URN)10.1006/viro.2002.1428 (DOI)12083821 (PubMedID)
    Tillgänglig från: 2002-05-10 Skapad: 2002-05-10 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    4. ERV3 and related sequences in humans; studies of RNA expression by real-time PCR and in situ hybridisation
    Öppna denna publikation i ny flik eller fönster >>ERV3 and related sequences in humans; studies of RNA expression by real-time PCR and in situ hybridisation
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-89900 (URN)
    Tillgänglig från: 2002-05-10 Skapad: 2002-05-10 Senast uppdaterad: 2010-01-13Bibliografiskt granskad
    5. ERV3 in relation to cell differentiation in normal and neoplastic monocytes
    Öppna denna publikation i ny flik eller fönster >>ERV3 in relation to cell differentiation in normal and neoplastic monocytes
    Visa övriga...
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-89901 (URN)
    Tillgänglig från: 2002-05-10 Skapad: 2002-05-10 Senast uppdaterad: 2010-01-13Bibliografiskt granskad
    Ladda ner fulltext (pdf)
    FULLTEXT01
  • 28.
    Andersson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.;Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX USA..
    Domestic animals as models for biomedical research2016Ingår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, nr 1, s. 1-11Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Domestic animals are unique models for biomedical research due to their long history (thousands of years) of strong phenotypic selection. This process has enriched for novel mutations that have contributed to phenotype evolution in domestic animals. The characterization of such mutations provides insights in gene function and biological mechanisms. This review summarizes genetic dissection of about 50 genetic variants affecting pigmentation, behaviour, metabolic regulation, and the pattern of locomotion. The variants are controlled by mutations in about 30 different genes, and for 10 of these our group was the first to report an association between the gene and a phenotype. Almost half of the reported mutations occur in non-coding sequences, suggesting that this is the most common type of polymorphism underlying phenotypic variation since this is a biased list where the proportion of coding mutations are inflated as they are easier to find. The review documents that structural changes (duplications, deletions, and inversions) have contributed significantly to the evolution of phenotypic diversity in domestic animals. Finally, we describe five examples of evolution of alleles, which means that alleles have evolved by the accumulation of several consecutive mutations affecting the function of the same gene.

  • 29.
    Andersson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Swedish Univ Agr Sci, Uppsala, Sweden;Texas A&M Univ, College Stn, TX 77843 USA.
    Fisher's quantitative genetic model and the molecular genetics of multifactorial traits2018Ingår i: Journal of Animal Breeding and Genetics, ISSN 0931-2668, E-ISSN 1439-0388, Vol. 135, nr 6, s. 391-392Artikel i tidskrift (Övrigt vetenskapligt)
  • 30.
    Andersson, S
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för evolutionsbiologi.
    Differences in the genetic basis of leaf dissectin between two populations of Crepis tectorum (Asteraceae).1995Ingår i: Heredity, Vol. 75, s. 62-69Artikel i tidskrift (Refereegranskat)
  • 31.
    Andersson, S
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för evolutionsbiologi.
    Quantitative genetics of leaf morphology in Crepis tectorum ssp. pumila (Asteraceae).1999Ingår i: J Hered, Vol. 90, s. 556-561Artikel i tidskrift (Refereegranskat)
  • 32.
    Andrae, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    Gouveia, Maria Leonor Seguardo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    He, Liqun
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    Betsholtz, Christer
    Characterization of Platelet-Derived Growth Factor-A Expression in Mouse Tissues Using a lacZ Knock-In Approach2014Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 9, nr 8, s. e105477-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Expression of the platelet-derived growth factor A-chain gene (Pdgfa) occurs widely in the developing mouse, where it is mainly localized to various epithelial and neuronal structures. Until now, in situ mRNA hybridization (ISH) has been the only reliable method to identify Pdgfa expression in tissue sections or whole mount preparations. Validated protocols for in situ detection of PDGF-A protein by immunohistochemistry is lacking. In particular, this has hampered understanding of Pdgfa expression pattern in adult tissues, where ISH is technically challenging. Here, we report a gene targeted mouse Pdgfa allele, Pdgfa(ex4COIN), which is a combined conditional knockout and reporter allele. Cre-mediated inversion of the COIN cassette inactivates Pdgfa coding while simultaneously activating a beta-galactosidase (lacZ) reporter under endogenous Pdgfa transcription control. The generated Pdgfa(ex4COIN-INV-lacZ) allele can next be used to identify cells carrying a Pdgfa null allele, as well as to map endogenous Pdgfa expression. We evaluated the Pdgfa(ex4COIN-INV-lacZ) allele as a reporter for endogenous Pdgfa expression patterns in mouse embryos and adults. We conclude that the expression pattern of Pdgfa(ex4COIN-INV-lacZ) recapitulates known expression patterns of Pdgfa. We also report on novel embryonic and adult Pdgfa expression patterns in the mouse and discuss their implications for Pdgfa physiology.

    Ladda ner fulltext (pdf)
    fulltext
  • 33.
    Andræ, Johanna
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    PDGF in cerebellar development and tumorigenesis2001Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Medulloblastoma is a highly malignant cerebellar childhood tumor. As in many other brain tumors, expression of platelet-derived growth factor (PDGF) and its receptors has been shown in medulloblastoma. To reveal the importance of this growth factor in cerebellar development and tumorigenesis, analyses were performed on human medulloblastoma cell lines and on tissue from normal mouse brain at different stages of development. The in vivo effect of a forced expression of PDGF-B in the cerebellar primordium was examined in transgenic mice.

    In the normal mouse embryo, we found PDGF receptor-α-positive cells in the early neuroepithelium and on neuronal precursors. In the postnatal cerebellum, cells in the external germinal layer and Purkinje cells expressed the receptor. In the medulloblastoma cells, expression of all the three PDGF isoforms and PDGF receptors was seen and correlated to neuronal differentiation. Endogenously activated, i.e. tyrosine phosphorylated, PDGF receptors were identified. To reveal the role of PDGF in normal cerebellar development, we established transgenic mice where a PDGF-B cDNA was introduced via homologous recombination into the engrailed-1 gene. Engrailed-1 is specifically expressed at the mid-/hindbrain boundary of the early neural tube, i.e. in an area from which the cerebellar primordium develops. The ectopic expression of PDGF-B caused a disturbance of cerebellar development. Midline fusion of the cerebellar primordium did not occur properly, which resulted in cerebellar dysplasia in the adult mouse.

    In a parallel study, the expression pattern of a glial fibrillary acidic protein (GFAP)-lacZ transgene was followed in the embryonic mouse central nervous system. It was shown that the human GFAP promoter was already active by embryonic day 9.5 and as development proceeded, expression occured in different, independent cell populations. Among these cell populations were the radial glial cells in the neocortex.

    Ladda ner fulltext (pdf)
    FULLTEXT01
  • 34.
    Andréasson, Hanna
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Sensitive Forensic DNA Analysis: Application of Pyrosequencing and Real-time PCR Quantification2005Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The field of forensic genetics is growing fast and the development and optimisation of more sensitive, faster and more discriminating forensic DNA analysis methods is highly important. In this thesis, an evaluation of the use of novel DNA technologies and the development of specific applications for use in forensic casework investigations are presented.

    In order to maximise the use of valuable limited DNA samples, a fast and user-friendly Real-time PCR quantification assay, of nuclear and mitochondrial DNA copies, was developed. The system is based on the 5’ exonuclease detection assay and was evaluated and successfully used for quantification of a number of different evidence material types commonly found on crime scenes. Furthermore, a system is described that allows both nuclear DNA quantification and sex determination in limited samples, based on intercalation of the SYBR Green dye to double stranded DNA.

    To enable highly sensitive DNA analysis, Pyrosequencing of short stretches of mitochondrial DNA was developed. The system covers both control region and coding region variation, thus providing increased discrimination power for mitochondrial DNA analysis. Finally, due to the lack of optimal assays for quantification of mitochondrial DNA mixture, an alternative use of the Pyrosequencing system was developed. This assay allows precise ratio quantification of mitochondrial DNA in samples showing contribution from more than one individual.

    In conclusion, the development of optimised forensic DNA analysis methods in this thesis provides several novel quantification assays and increased knowledge of typical DNA amounts in various forensic samples. The new, fast and sensitive mitochondrial DNA Pyrosequencing assay was developed and has the potential for increased discrimination power.

    Delarbeten
    1.
    Posten kunde inte hittas. Det kan bero på att posten inte längre är tillgänglig eller att du har råkat ange ett felaktigt id i adressfältet.
    2. Nuclear and mitochondrial DNA quantification of various forensic materials
    Öppna denna publikation i ny flik eller fönster >>Nuclear and mitochondrial DNA quantification of various forensic materials
    2006 (Engelska)Ingår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 164, nr 1, s. 56-64Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Due to the different types and quality of forensic evidence materials, their DNA content can vary substantially, and particularly low quantities can impact the results in an identification analysis. In this study, the quantity of mitochondrial and nuclear DNA was determined in a variety of materials using a previously described real-time PCR method. DNA quantification in the roots and distal sections of plucked and shed head hairs revealed large variations in DNA content particularly between the root and the shaft of plucked hairs. Also large intra- and inter-individual variations were found among hairs. In additions DNA content was estimated in samples collected from fingerprints and accessories. The quantification of DNA on various items also displayed large variations, with some materials containing large amounts of nuclear DNA while no detectable nuclear DNA and only limited amounts of mitochondrial DNA were seen in others. Using this sensitive real-time PCR quantification assay, a better understanding was obtained regarding DNA content and variation in commonly analysed forensic evidence materials and this may guide the forensic scientist as to the best molecular biology approach for analysing various forensic evidence materials.

    Nyckelord
    quantification, real-time PCR, forensic materials, hair, nuclear DNA, mitochondrial DNA
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-92985 (URN)10.1016/j.forsciint.2005.11.024 (DOI)000242666700006 ()16427750 (PubMedID)
    Tillgänglig från: 2005-04-29 Skapad: 2005-04-29 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    3. Rapid quantification and sex determination of forensic evidence materials
    Öppna denna publikation i ny flik eller fönster >>Rapid quantification and sex determination of forensic evidence materials
    2003 (Engelska)Ingår i: Journal of Forensic Sciences, ISSN 0022-1198, E-ISSN 1556-4029, Vol. 48, nr 6, s. 1280-1287Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    DNA quantification of forensic evidence is very valuable for an optimal use of the available biological material. Moreover, sex determination is of great importance as additional information in criminal investigations as well as in identification of missing persons, no suspect cases, and ancient DNA studies. While routine forensic DNA analysis based on short tandem repeat markers includes a marker for sex determination, analysis of samples containing scarce amounts of DNA is often based on mitochondrial DNA, and sex determination is not performed. In order to allow quantification and simultaneous sex determination on minute amounts of DNA, an assay based on real-time PCR analysis of a marker within the human amelogenin gene has been developed. The sex determination is based on melting curve analysis, while an externally standardized kinetic analysis allows quantification of the nuclear DNA copy number in the sample. This real-time DNA quantification assay has proven to be highly sensitive, enabling quantification of single DNA copies. Although certain limitations were apparent, the system is a rapid, cost-effective, and flexible assay for analysis of forensic casework samples.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-92986 (URN)14640271 (PubMedID)
    Tillgänglig från: 2005-04-29 Skapad: 2005-04-29 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    4. Mitochondrial sequence analysis for forensic identification using Pyrosequencing technology
    Öppna denna publikation i ny flik eller fönster >>Mitochondrial sequence analysis for forensic identification using Pyrosequencing technology
    Visa övriga...
    2002 (Engelska)Ingår i: BioTechniques, ISSN 0736-6205, E-ISSN 1940-9818, Vol. 32, nr 1, s. 124-6, 128, 130-3Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Over recent years, requests for mtDNA analysis in the field of forensic medicine have notably increased, and the results of such analyses have proved to be very useful in forensic cases where nuclear DNA analysis cannot be performed. Traditionally, mtDNA has been analyzed by DNA sequencing of the two hypervariable regions, HVI and HVII, in the D-loop. DNA sequence analysis using the conventional Sanger sequencing is very robust but time consuming and labor intensive. By contrast, mtDNA analysis based on the pyrosequencing technology provides fast and accurate results from the human mtDNA present in many types of evidence materials in forensic casework. The assay has been developed to determine polymorphic sites in the mitochondrial D-loop as well as the coding region to further increase the discrimination power of mtDNA analysis. The pyrosequencing technology for analysis of mtDNA polymorphisms has been tested with regard to sensitivity, reproducibility, and success rate when applied to control samples and actual casework materials. The results show that the method is very accurate and sensitive; the results are easily interpreted and provide a high success rate on casework samples. The panel of pyrosequencing reactions for the mtDNA polymorphisms were chosen to result in an optimal discrimination power in relation to the number of bases determined.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-92987 (URN)11808686 (PubMedID)
    Tillgänglig från: 2005-04-29 Skapad: 2005-04-29 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    5. Coding mtDNA analysis for increased forensic discrimination power using Pyrosequencing technology
    Öppna denna publikation i ny flik eller fönster >>Coding mtDNA analysis for increased forensic discrimination power using Pyrosequencing technology
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-92988 (URN)
    Tillgänglig från: 2005-04-29 Skapad: 2005-04-29 Senast uppdaterad: 2010-01-13Bibliografiskt granskad
    6. Quantification of mtDNA mixtures in forensic evidence material using pyrosequencing
    Öppna denna publikation i ny flik eller fönster >>Quantification of mtDNA mixtures in forensic evidence material using pyrosequencing
    Visa övriga...
    2006 (Engelska)Ingår i: International journal of legal medicine, ISSN 0937-9827, E-ISSN 1437-1596, Vol. 120, nr 6, s. 383-390Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Analysis of mtDNA variation using Sanger sequencing does not allow accurate quantification of the components of mtDNA mixtures. An alternative method to determine the specific mixture ratios in samples displaying heteroplasmy, consisting of DNA contributions from several individuals, or containing contamination would therefore be valuable. A novel quantification system for mtDNA mixture analysis has been developed based on pyrosequencing technology, in which the linear relationship between incorporated nucleotides and released light allows quantification of the components of a sample. Within five polymerase chain reaction fragments, seven variable positions in the mtDNA control and coding region were evaluated using this quantification analysis. For all single nucleotide polymorphisms quantified in this study, a linear relationship was observed between the measured and expected mixture ratios. This mtDNA quantification assay is an easy to use, fast and accurate quantification system, with the ability to resolve and interpret major and minor mtDNA components in forensic mixture samples.

    Nyckelord
    mixtures, mitochondrial DNA, pyrosequencing, quantification, forensic material
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-92989 (URN)10.1007/s00414-005-0072-8 (DOI)000241522300013 ()16453148 (PubMedID)
    Tillgänglig från: 2005-04-29 Skapad: 2005-04-29 Senast uppdaterad: 2024-01-17Bibliografiskt granskad
    Ladda ner fulltext (pdf)
    FULLTEXT01
    Ladda ner (pdf)
    COVER01
  • 35.
    Angius, Andrea
    et al.
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy.
    Uva, Paolo
    Ctr Adv Studies Res & Dev Sardinia CRS4, Sci & Technol Pk Polaris, Pula, Italy.
    Oppo, Manuela
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy;Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy.
    Buers, Insa
    Munster Univ, Cells Mot Cluster Excellence, Munster, Germany;Munster Univ, Childrens Hosp, Dept Gen Pediat, Munster, Germany.
    Persico, Ivana
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy.
    Onano, Stefano
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy;Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy.
    Cuccuru, Gianmauro
    Ctr Adv Studies Res & Dev Sardinia CRS4, Sci & Technol Pk Polaris, Pula, Italy.
    Van Allen, Margot I.
    Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada;BC Childrens & Womens Hlth Ctr, Prov Hlth Serv Author, Vancouver, BC, Canada;Victoria Isl Hlth Author, Dept Med Genet, Victoria, BC, Canada.
    Hulait, Gurdip
    BC Childrens & Womens Hlth Ctr, Prov Hlth Serv Author, Vancouver, BC, Canada.
    Aubertin, Gudrun
    Victoria Isl Hlth Author, Dept Med Genet, Victoria, BC, Canada.
    Muntoni, Francesco
    UCL Great Ormond St Hosp, Dubowitz Neuromuscular Ctr, London, England;Univ Hosp Wales, Inst Med Genet, Cardiff, S Glam, Wales.
    Fry, Andrew E.
    Annerén, Göran
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Stattin, Evalena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Palomares-Bralo, Maria
    Santos-Simarro, Fernando
    Cucca, Francesco
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy;Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy.
    Crisponi, Giangiorgio
    Clin St Anna, Cagliari, Italy.
    Rutsch, Frank
    Munster Univ, Cells Mot Cluster Excellence, Munster, Germany;Munster Univ, Childrens Hosp, Dept Gen Pediat, Munster, Germany.
    Crisponi, Laura
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy;Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy.
    Exome sequencing in Crisponi/cold-induced sweating syndrome-like individuals reveals unpredicted alternative diagnoses2019Ingår i: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 95, nr 5, s. 607-614Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by a complex phenotype (hyperthermia and feeding difficulties in the neonatal period, followed by scoliosis and paradoxical sweating induced by cold since early childhood) and a high neonatal lethality. CS/CISS is a genetically heterogeneous disorder caused by mutations in CRLF1 (CS/CISS1), CLCF1 (CS/CISS2) and KLHL7 (CS/CISS-like). Here, a whole exome sequencing approach in individuals with CS/CISS-like phenotype with unknown molecular defect revealed unpredicted alternative diagnoses. This approach identified putative pathogenic variations in NALCN, MAGEL2 and SCN2A. They were already found implicated in the pathogenesis of other syndromes, respectively the congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome, the Schaaf-Yang syndrome, and the early infantile epileptic encephalopathy-11 syndrome. These results suggest a high neonatal phenotypic overlap among these disorders and will be very helpful for clinicians. Genetic analysis of these genes should be considered for those cases with a suspected CS/CISS during neonatal period who were tested as mutation negative in the known CS/CISS genes, because an expedited and corrected diagnosis can improve patient management and can provide a specific clinical follow-up.

  • 36. Anthoni, Heidi
    et al.
    Zucchelli, Marco
    Matsson, Hans
    Müller-Myhsok, Bertram
    Fransson, Ingegerd
    Schumacher, Johannes
    Massinen, Satu
    Onkamo, Päivi
    Warnke, Andreas
    Griesemann, Heide
    Hoffmann, Per
    Nopola-Hemmi, Jaana
    Lyytinen, Heikki
    Schulte-Körne, Gerd
    Kere, Juha
    Nöthen, Markus M
    Peyrard-Janvid, Myriam
    A locus on 2p12 containing the co-regulated MRPL19 and C2ORF3 genes is associated to dyslexia.2007Ingår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 16, nr 6, s. 667-77Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    DYX3, a locus for dyslexia, resides on chromosome 2p11-p15. We have refined its location on 2p12 to a 157 kb region in two rounds of linkage disequilibrium (LD) mapping in a set of Finnish families. The observed association was replicated in an independent set of 251 German families. Two overlapping risk haplotypes spanning 16 kb were identified in both sample sets separately as well as in a joint analysis. In the German sample set, the odds ratio for the most significantly associated haplotype increased with dyslexia severity from 2.2 to 5.2. The risk haplotypes are located in an intergenic region between FLJ13391 and MRPL19/C2ORF3. As no novel genes could be cloned from this region, we hypothesized that the risk haplotypes might affect long-distance regulatory elements and characterized the three known genes. MRPL19 and C2ORF3 are in strong LD and were highly co-expressed across a panel of tissues from regions of adult human brain. The expression of MRPL19 and C2ORF3, but not FLJ13391, were also correlated with the four dyslexia candidate genes identified so far (DYX1C1, ROBO1, DCDC2 and KIAA0319). Although several non-synonymous changes were identified in MRPL19 and C2ORF3, none of them significantly associated with dyslexia. However, heterozygous carriers of the risk haplotype showed significantly attenuated expression of both MRPL19 and C2ORF3, as compared with non-carriers. Analysis of C2ORF3 orthologues in four non-human primates suggested different evolutionary rates for primates when compared with the out-group. In conclusion, our data support MRPL19 and C2ORF3 as candidate susceptibility genes for DYX3.

  • 37.
    Antson, Dan-Oscar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Genotyping RNA and DNA using padlock probes2001Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Novel techniques are needed to investigate the genetic variation revealed in the first draft of the human genome sequence. Padlock probes are recently developed reagents, suitable for detecting single-nucleotide variations of DNA and RNA in situ or in solution. The probes are oligonucleotides of about 70-140 nucleotides that can be circularized by ligation in the presence of a correct target sequence. Standard chemical synthesis of padlock probes is difficult due to the requirement for intact 5' and 3' ends of these long oligonucleotides.

    A novel PCR-based method is presented in this thesis, whereby longer, densely labeled padlock probes can be made as compared to conventional chemical synthesis. PCR-generated padlock probes produced a stronger signal and a more resolved staining pattern, compared to chemically synthesized probes in fluorescence in situ analysis of an alpha-satellite sequence variant present in human chromosomes 13 and 21. Padlock probes used for in situ analysis of metaphase chromosomes had an optimal length of 140 nucleotides. They were used to identify individual chromosomes 7 and 15, and to follow the transmission of chromosome homologues for two consecutive generations. The specificity of the padlock probes to detect single copy genes in genomic DNA samples was demonstrated by detecting a single-nucleotide mutation in the ATP7B gene.

    It has not previously been known if T4 DNA ligase can be used for RNA sequence analysis. In this thesis, it is demonstrated that T4 DNA ligase can be used for distinguishing single-nucleotide RNA sequence variants. Reaction conditions were defined where most mismatches could be discriminated by a factor of 80 and all mismatches by a factor of at least 20. Under these conditions padlock probes could detect and distinguish RNA sequence variants with ligation efficiency almost as high as on the corresponding DNA sequence.

    A detailed study of the parameters influencing RNA-templated DNA ligation revealed that DNA ligation on RNA templates proceeds at a much slower rate compared to the same reaction on DNA, and that a molar excess of enzyme is required. Furthermore, the ligation reaction is inhibited by high concentrations of the cofactor ATP and NaCl.

    The work presented in this thesis demonstrates that PCR-generated padlock probes can detect and distinguish single-nucleotide variation in both RNA and DNA.

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  • 38.
    Aoun, Mike
    et al.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Coelho, Ana
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Kraemer, Alexander
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Saxena, Amit
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Sabatier, Pierre
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 1, Solna, Sweden..
    Beusch, Christian Michel
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 1, Solna, Sweden..
    Loennblom, Erik
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Geng, Manman
    Xian JiaotongUniv, Precis Med Inst, Affiliated Hosp 2, Xian, Peoples R China..
    Do, Nhu-Nguyen
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden.;Fraunhofer Inst Translat Med & Pharmacol, Frankfurt, Germany.;Fraunhofer Cluster Excellence Immune Mediated Dis, Frankfurt, Germany..
    Xu, Zhongwei
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Zhang, Jingdian
    Karolinska Inst, Max Planck Inst Biol Ageing, Karolinska Inst Lab, Solna, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, Div Mol Metab, Solna, Sweden..
    He, Yibo
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Romero Castillo, Laura
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Abolhassani, Hassan
    Karolinska Univ Hosp, Karolinska Inst, Dept Biosci & Nutr, Div Clin Immunol, Neo Bldg, Solna, Sweden..
    Xu, Bingze
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Viljanen, Johan V.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Rorbach, Joanna
    Karolinska Inst, Max Planck Inst Biol Ageing, Karolinska Inst Lab, Solna, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, Div Mol Metab, Solna, Sweden..
    Fernandez Lahore, Gonzalo
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden..
    Gjertsson, Inger
    Univ Gothenburg, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden..
    Kastbom, Alf
    Linköping Univ, Dept Biomed & Clin Sci, Div Inflammat & Infect, Linköping, Sweden..
    Sjoewall, Christopher
    Linköping Univ, Dept Biomed & Clin Sci, Div Inflammat & Infect, Linköping, Sweden..
    Kihlberg, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Zubarev, Roman A.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 1, Solna, Sweden.;IM Sechenov First Moscow State Med Univ, Dept Pharmacol & Technol Chem, Moscow, Russia..
    Burkhardt, Harald
    Fraunhofer Inst Translat Med & Pharmacol, Frankfurt, Germany.;Fraunhofer Cluster Excellence Immune Mediated Dis, Frankfurt, Germany.;Goethe Univ, Univ Hosp Frankfurt, Div Rheumatol, Frankfurt am Main, Germany..
    Holmdahl, Rikard
    Karolinska Inst, Dept Med Biochem & Biophys, Div Med Inflammat Res, Solna, Sweden.;Xian JiaotongUniv, Precis Med Inst, Affiliated Hosp 2, Xian, Peoples R China..
    Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice2023Ingår i: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 220, nr 11, artikel-id e20230101Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    B cells undergo several rounds of selection to eliminate potentially pathogenic autoreactive clones, but in contrast to T cells, evidence of positive selection of autoreactive B cells remains moot. Using unique tetramers, we traced natural autoreactive B cells (C1-B) specific for a defined triple-helical epitope on collagen type-II (COL2), constituting a sizeable fraction of the physiological B cell repertoire in mice, rats, and humans. Adoptive transfer of C1-B suppressed arthritis independently of IL10, separating them from IL10-secreting regulatory B cells. Single-cell sequencing revealed an antigen processing and presentation signature, including induced expression of CD72 and CCR7 as surface markers. C1-B presented COL2 to T cells and induced the expansion of regulatory T cells in a contact-dependent manner. CD72 blockade impeded this effect suggesting a new downstream suppressor mechanism that regulates antigen-specific T cell tolerization. Thus, our results indicate that autoreactive antigen-specific naive B cells tolerize infiltrating T cells against self-antigens to impede the development of tissue-specific autoimmune inflammation.

  • 39.
    Arendt, Maja Louise
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Univ Copenhagen, Fac Hlth & Med Sci, Dept Vet Clin Sci, Copenhagen, Denmark..
    Ambrosen, Aime
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Kierczak, Marcin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution.
    Tengvall, Katarina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Meadows, Jennifer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Karlsson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lagerstedt, Anne-Sofie
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Bergström, Tomas
    Andersson, Göran
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Lindblad-Toh, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Hagman, Ragnvi
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    The ABCC4 gene is associated with pyometra in golden retriever dogs2021Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 11, artikel-id 16647Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pyometra is one of the most common diseases in female dogs, presenting as purulent inflammation and bacterial infection of the uterus. On average 20% of intact female dogs are affected before 10 years of age, a proportion that varies greatly between breeds (3-66%). The clear breed predisposition suggests that genetic risk factors are involved in disease development. To identify genetic risk factors associated with the disease, we performed a genome-wide association study (GWAS) in golden retrievers, a breed with increased risk of developing pyometra (risk ratio: 3.3). We applied a mixed model approach comparing 98 cases, and 96 healthy controls and identified an associated locus on chromosome 22 (p = 1.2 x 10(-6), passing Bonferroni corrected significance). This locus contained five significantly associated SNPs positioned within introns of the ATP-binding cassette transporter 4 (ABCC4) gene. This gene encodes a transmembrane transporter that is important for prostaglandin transport. Next generation sequencing and genotyping of cases and controls subsequently identified four missense SNPs within the ABCC4 gene. One missense SNP at chr22:45,893,198 (p.Met787Val) showed complete linkage disequilibrium with the associated GWAS SNPs suggesting a potential role in disease development. Another locus on chromosome 18 overlapping the TESMIN gene, is also potentially implicated in the development of the disease.

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  • 40. Arkani, Samara
    et al.
    Cao, Jia
    Lundin, Johanna
    Nilsson, Daniel
    Källman, Thomas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Växtekologi och evolution. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Barker, Gillian
    Holmdahl, Gundela
    Clementsson Kockum, Christina
    Matsson, Hans
    Nordenskjöld, Agneta
    Evaluation of the ISL1 gene in the pathogenesis of bladder exstrophy in a Swedish cohort2018Ingår i: Human genome variation, ISSN 2054-345X, Vol. 5, nr 1, artikel-id 18009Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Bladder exstrophy is a congenital closure defect of the urinary bladder with a profound effect on morbidity. Although the malformation is usually sporadic, a genetic background is supported by an increased recurrence risk in relatives, higher concordance rates in monozygotic twins and several associated chromosomal aberrations. Recently, the ISL1 gene was presented as a candidate gene for bladder exstrophy and epispadias complex (BEEC) development in two different studies. In our study, we screened for genetic variants in the ISL1 gene in DNA from 125 Swedish patients using Sanger sequencing and array-CGH analysis. In addition, we evaluated ISL1 expression in RNA of human bladder during embryonic and fetal weeks 5–10 relative to that in lung tissue (week 9). In total, 21 single-nucleotide variants were identified, including a potentially novel missense variant, c.137C>G p.(Ala46Gly), substituting a conserved amino acid. This variant was inherited from an unaffected mother. No structural variants were identified. RNA sequencing revealed ISL1 mRNA expression during the critical time frame of human bladder development. In conclusion, we did not detect any known or likely pathogenic variants in the ISL1 gene in 125 Swedish BEEC patients, indicating that variation in the ISL1 gene is not a common genetic mechanism of BEEC development in the Swedish population.

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  • 41.
    Artemenko, Konstantin A.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    Lind, Sara Bergström
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Elfineh, Lioudmila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Mayrhofer, Corina
    Zubarev, Roman A.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    Pettersson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Optimization of immunoaffinity enrichment and detection: toward a comprehensive characterization of the phosphotyrosine proteome of K562 cells by liquid chromatography-mass spectrometry2011Ingår i: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 136, nr 9, s. 1971-1978Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Phosphorylation of protein tyrosine residues regulates many cell functions and has also been proved to be involved in oncogenesis. Thus, the identification of the phosphotyrosine (pTyr) proteome of cells is a very important task. Since tyrosine phosphorylation represents only around 1% of the total human phosphoproteome, the study of pTyr proteins is rather challenging. Here we report the optimization study of the phosphotyrosine proteome using K562 cells as a model system. A substantial segment of the phosphotyrosine proteome of K562 cells was characterized by immunoaffinity enrichment with 4G10 and PYKD1 antibodies followed by LC-MS/MS analysis. 480 non-redundant pTyr peptides corresponding to 342 pTyr proteins were found. 141 pTyr peptides were not described elsewhere. The mass spectrometry approach involving high-resolving FTMS analysis of precursor ions and subsequent detection of CID fragments in a linear ion trap was considered as optimal. For detection of low abundant pTyr peptides pooling of individual immunoaffinity enrichments for one LC-MS/MS analysis was crucial. The enrichment properties of the monoclonal PYKD1 antibody were presented for the first time, also in comparison to the 4G10 antibody. PYKD1 was found to be more effective for protein enrichment (1.2 and 5% efficiency at peptide and protein level correspondingly), while 4G10 showed better results when peptide enrichment was performed (15% efficiency versus 3.6% at protein level). Substantially different subsets of the phosphoproteome were enriched by these antibodies. This finding together with previous studies demonstrates that comprehensive pTyr proteome characterization by immunoprecipitation requires multiple antibodies to be used for the affinity enrichment.

  • 42.
    Aspegren, Anders
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Nuclear Organization of Gene Expression in Adenovirus Infected Cells2001Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Adenovirus infected cells provide a good model system for studying nuclear organization during RNA production and transport. This thesis is focused on the dynamic organization of splicing factors during the late phase of Adenovirus infection in HeLa cells, the nuclear localization of viral RNA, and the pathway used for viral RNA transport to the cytoplasm.

    Splicing factors are relocalized from interchromatin granule clusters to sites of transcription in Adenovirus infected cells at intermediate times of infection. Later, splicing factors and viral RNA accumulate posttranscriptionally in interchromatin granule clusters. The release of the splicing factors from transcription sites was energy dependent or preceded by energy requiring mechanisms. Our data indicated that phosphorylation events inhibited by staurosporine, and 3' cleavage of the transcript are two possible mechanisms involved prior to the release of the RNP complex from transcription sites.

    A viral protein derived from orf6 of early region 4, 34K, is important for the nuclear stability and transport of late viral mRNA derived from the major late transcription unit. A viral mutant lacking this region is defective for posttranscriptional accumulation of viral mRNA in interchromatin granule clusters, and for the accumulation of viral RNA in the cytoplasm. These results suggest that posttranscriptional accumulation of viral RNA in interchromatin granule clusters may contribute to the maturation of the RNP complex or sorting of RNAs and proteins, to prepare the final RNP complex for transport to the cytoplasm.

    A previous model suggested that adenoviral late mRNA is transported to the cytoplasm by utilizing the CRM-1 pathway. This pathway can be blocked by the drug leptomycin B. The data presented in paper IV suggests that this model might not be applicable, since leptomycin B did not inhibit adenoviral late gene expression.

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  • 43.
    Asplund, Olof
    et al.
    Lund Univ, Dept Clin Sci, Diabet Ctr, Genom Diabet & Endocrinol Unit, Jan Waldenströms Gata 35, S-20502 Malmö, Sweden.
    Rung, Johan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Groop, Leif
    Lund Univ, Dept Clin Sci, Diabet Ctr, Genom Diabet & Endocrinol Unit, Jan Waldenströms Gata 35, S-20502 Malmö, Sweden; Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki 800290, Finland.
    Prasad, Rashmi B.
    Lund Univ, Dept Clin Sci, Diabet Ctr, Genom Diabet & Endocrinol Unit, Jan Waldenströms Gata 35, S-20502 Malmö, Sweden.
    Hansson, Ola
    Lund Univ, Dept Clin Sci, Diabet Ctr, Genom Diabet & Endocrinol Unit, Jan Waldenströms Gata 35, S-20502 Malmö, Sweden; Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki 800290, Finland.
    MuscleAtlasExplorer: a web service for studying gene expression in human skeletal muscle2020Ingår i: Database: The Journal of Biological Databases and Curation, E-ISSN 1758-0463, Vol. 2020, artikel-id baaa111Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    MuscleAtlasExplorer is a freely available web application that allows for the exploration of gene expression data from human skeletal muscle. It draws from an extensive publicly available dataset of 1654 skeletal muscle expression microarray samples. Detailed, manually curated, patient phenotype data, with information such as age, sex, BMI and disease status, are combined with skeletal muscle gene expression to provide insights into gene function in skeletal muscle. It aims to facilitate easy exploration of the data using powerful data visualization functions, while allowing for sample selection, in-depth inspection and further analysis using external tools.

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  • 44. Astuti, D
    et al.
    Latif, F
    Dallol, A
    Dahia, P L
    Douglas, F
    George, E
    Sköldberg, Filip
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Gastrointestinalkirurgi.
    Husebye, E S
    Eng, C
    Maher, E R
    Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.2001Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 69, nr 1, s. 49-54Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The pheochromocytomas are an important cause of secondary hypertension. Although pheochromocytoma susceptibility may be associated with germline mutations in the tumor-suppressor genes VHL and NF1 and in the proto-oncogene RET, the genetic basis for most cases of nonsyndromic familial pheochromocytoma is unknown. Recently, pheochromocytoma susceptibility has been associated with germline SDHD mutations. Germline SDHD mutations were originally described in hereditary paraganglioma, a dominantly inherited disorder characterized by vascular tumors in the head and the neck, most frequently at the carotid bifurcation. The gene products of two components of succinate dehydrogenase, SDHC and SDHD, anchor the gene products of two other components, SDHA and SDHB, which form the catalytic core, to the inner-mitochondrial membrane. Although mutations in SDHC and in SDHD may cause hereditary paraganglioma, germline SDHA mutations are associated with juvenile encephalopathy, and the phenotypic consequences of SDHB mutations have not been defined. To investigate the genetic causes of pheochromocytoma, we analyzed SDHB and SDHC, in familial and in sporadic cases. Inactivating SDHB mutations were detected in two of the five kindreds with familial pheochromocytoma, two of the three kindreds with pheochromocytoma and paraganglioma susceptibility, and 1 of the 24 cases of sporadic pheochromocytoma. These findings extend the link between mitochondrial dysfunction and tumorigenesis and suggest that germline SDHB mutations are an important cause of pheochromocytoma susceptibility.

  • 45.
    Ata, Ahmad Khaled
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Expression of TGF- isoforms, their receptors and related SMAD proteins in brain pathology: Immunohistochemical studies focusing on infarcts, abscesses and malignant gliomas1999Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    This thesis focuses on the immunohistochemical expression of transforming growth factor beta(TGFβ) isoforms, their receptors and TGF-β-related SMAD proteins in brain pathology, chiefly in-farcts. One key question was whether the expressions of these compounds are altered within glial cells, endothelial cells of microvessels and other cell types in the vicinity of infarcts. Studies on human and animal brain infarcts were made. Immunoreactivities to TGF-β isoforms -β1, -β2 and -β3, and TGF-βreceptor (TβR) type I were seen in astrocytes, macrophages, neurons, endothelial and vascular smooth muscle cells of human brain infarcts. Similar observations were made in an experimental model of rat brain infarct at day 1 and 3 following occlusion of the middle cerebral artery (MCA). Increased expression of Smad2, -3, -4, -6 and -7 was seen already at 6 h after MCA occlusion in neurons, microvascular endothelial cells, astroglial cells and inflammatory cells. Later on, immunopositive macrophages were present in the infarcts. The changes persisted even at day 7 after MCA occlusion.

    Several alterations thus occur during the evolution of brain infarcts with regard to the immuno­histochemical expression of TGF-β, its receptors and related SMAD proteins. Such changes are, however, not unique to brain infarcts. Thus, patterns of high expression for TGF-β- isoforms -β1, -β2 -β3, and TβR-I in cases of brain abscess (human), and of Smad2, -3, -4, -6 and -7 in tumor cells and neoplastic blood vessels of malignant gliomas (human) were also observed.

    In addition, immunohistochemical expression of vascular endothelial growth factor (VEGF) andits receptors was investigated since this growth factor is involved in angiogenesis and edemaformation, two cardinal features of brain infarcts. Increased immunoreactivities, seen particularly in the edges of infarcts, were observed already at day 1 after MCA occlusion.

    In conclusion, the various TGF-β isoforms, receptors and related SMAD proteins, together with other factors, seem to be involved in the very complicated and important changes taking place in the vicinity of brain infarcts.

  • 46. Ayoglu, Burcu
    et al.
    Chaouch, Amina
    Lochmueller, Hanns
    Politano, Luisa
    Bertini, Enrico
    Spitali, Pietro
    Hiller, Monika
    Niks, Eric H.
    Gualandi, Francesca
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bushby, Kate
    Aartsma-Rus, Annemieke
    Schwartz, Elena
    Le Priol, Yannick
    Straub, Volker
    Uhlen, Mathias
    Cirak, Sebahattin
    't Hoen, Peter A. C.
    Muntoni, Francesco
    Ferlini, Alessandra
    Schwenk, Jochen M.
    Nilsson, Peter
    Szigyarto, Cristina Al-Khalili
    Affinity proteomics within rare diseases: a BIO-NMD study for blood biomarkers of muscular dystrophies2014Ingår i: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 6, nr 7, s. 918-936Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite the recent progress in the broad-scaled analysis of proteins in body fluids, there is still a lack in protein profiling approaches for biomarkers of rare diseases. Scarcity of samples is the main obstacle hindering attempts to apply discovery driven protein profiling in rare diseases. We addressed this challenge by combining samples collected within the BIO-NMD consortium from four geographically dispersed clinical sites to identify protein markers associated with muscular dystrophy using an antibody bead array platform with 384 antibodies. Based on concordance in statistical significance and confirmatory results obtained from analysis of both serum and plasma, we identified eleven proteins associated with muscular dystrophy, among which four proteins were elevated in blood from muscular dystrophy patients: carbonic anhydrase III (CA3) and myosin light chain 3 (MYL3), both specifically expressed in slow-twitch muscle fibers and mitochondrial malate dehydrogenase 2 (MDH2) and electron transfer flavo-protein A (ETFA). Using age-matched sub-cohorts, 9 protein profiles correlating with disease progression and severity were identified, which hold promise for the development of new clinical tools for management of dystrophinopathies.

  • 47.
    Backman, Samuel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Molecular studies of endocrine tumors: Insights from genetics and epigenetics2020Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Endocrine tumors may be benign or malignant and may occur in any of the hormone producing tissues. They share several biological characteristics, including a low mutation-burden, and may co-occur in several hereditary tumor syndromes. The aim of this thesis was to identify genetic and epigenetic aberrations in endocrine tumors.

    In paper I we performed a comprehensive DNA methylation analysis of 39 pheochromocytomas/paragangliomas as well as 4 normal adrenal medullae on the HumanMethylation27 BeadChip array. We validated two previously described clusters based on DNA methylation with distinct genetic associations.

    In Paper II we performed a transcriptomic analysis of 15 aldosterone producing adenomas. CTNNB1-mutated tumors were found to form a distinct subgroup based on gene expression and to share gene expression similarities with non-aldosterone producing adrenocortical tumors with CTNNB1 mutations, including overexpression of AFF3 and ISM1.

    In paper III we used whole genome sequencing to identify germline genetic variants in 14 patients with Multiple Endocrine Neoplasia type 1 previously found to be wildtype for the MEN1 gene on routine clinical testing. Three patients were found to carry previously undetected MEN1 mutations. Two patients were confirmed to have phenocopies caused by variants affecting CASR or CDC73. In total 9/14 patients were not found to have a disease-causing germline variant, suggesting that the syndrome may in some cases be due to chance co-occurrence of several sporadic tumors.

    In paper IV RNA-Seq and whole genome sequencing of a cohort of SI-NETs selected on the basis of unusually short or long survival was performed in order to identify disease causing genes and potential prognostic factors. We confirmed known genetic aberrations and found rare variants in known cancer driver genes. Based on gene expression two clusters that differ in prognosis were detected. Moreover, through integration of copy number variation data and gene expression, we identied novel potential disease causing genes.

    Delarbeten
    1. Global DNA Methylation Analysis Identifies Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations
    Öppna denna publikation i ny flik eller fönster >>Global DNA Methylation Analysis Identifies Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations
    Visa övriga...
    2017 (Engelska)Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 7, artikel-id 44943Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Pheochromocytomas and paragangliomas (PPGLs) are rare and frequently heritable neural-crest derived tumours arising from the adrenal medulla or extra-adrenal chromaffin cells respectively. The majority of PPGL tumours are benign and do not recur with distant metastases. However, a sizeable fraction of these tumours secrete vasoactive catecholamines into the circulation causing a variety of symptoms including hypertension, palpitations and diaphoresis. The genetic landscape of PPGL has been well characterized and more than a dozen genes have been described as recurrently mutated. Recent studies of DNA-methylation have revealed distinct clusters of PPGL that share DNA methylation patterns and driver mutations, as well as identified potential biomarkers for malignancy. However, these findings have not been adequately validated in independent cohorts. In this study we use an array-based genome-wide approach to study the methylome of 39 PPGL and 4 normal adrenal medullae. We identified two distinct clusters of tumours characterized by different methylation patterns and different driver mutations. Moreover, we identify genes that are differentially methylated between tumour subcategories, and between tumours and normal tissue.

    Nationell ämneskategori
    Cancer och onkologi Kirurgi
    Identifikatorer
    urn:nbn:se:uu:diva-320646 (URN)10.1038/srep44943 (DOI)000397026500001 ()28327598 (PubMedID)
    Tillgänglig från: 2017-06-30 Skapad: 2017-06-30 Senast uppdaterad: 2022-09-15Bibliografiskt granskad
    2. RNA Sequencing Provides Novel Insights into the Transcriptome of Aldosterone Producing Adenomas
    Öppna denna publikation i ny flik eller fönster >>RNA Sequencing Provides Novel Insights into the Transcriptome of Aldosterone Producing Adenomas
    Visa övriga...
    2019 (Engelska)Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 9, artikel-id 6269Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Aldosterone producing adenomas (APAs) occur in the adrenal glands of around 30% of patients with primary aldosteronism, the most common form of secondary hypertension. Somatic mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D and CTNNB1 have been described in similar to 60% of these tumours. We subjected 15 aldosterone producing adenomas (13 with known mutations and two without) to RNA Sequencing and Whole Genome Sequencing (n = 2). All known mutations were detected in the RNA-Seq reads, and mutations in ATP2B3 (G123R) and CACNA1D (S410L) were discovered in the tumours without known mutations. Adenomas with CTNNB1 mutations showed a large number of differentially expressed genes (1360 compared to 106 and 75 for KCNJ5 and ATP1A1/ATP2B3 respectively) and clustered together in a hierarchical clustering analysis. RT-PCR in an extended cohort of 49 APAs confirmed higher expression of AFF3 and ISM1 in APAs with CTNNB1 mutations. Investigation of the expression of genes involved in proliferation and apoptosis revealed subtle differences between tumours with and without CTNNB1 mutations. Together our results consolidate the notion that CTNNB1 mutations characterize a distinct subgroup of APAs.

    Ort, förlag, år, upplaga, sidor
    NATURE PUBLISHING GROUP, 2019
    Nationell ämneskategori
    Endokrinologi och diabetes
    Identifikatorer
    urn:nbn:se:uu:diva-383193 (URN)10.1038/s41598-019-41525-2 (DOI)000465001600023 ()31000732 (PubMedID)
    Forskningsfinansiär
    VetenskapsrådetKnut och Alice Wallenbergs Stiftelse
    Anmärkning

    De två första författarna delar förstaförfattarskapet.

    Tillgänglig från: 2019-07-24 Skapad: 2019-07-24 Senast uppdaterad: 2022-09-15Bibliografiskt granskad
    3. Whole genome sequencing of apparently mutation-negative MEN1 patients
    Öppna denna publikation i ny flik eller fönster >>Whole genome sequencing of apparently mutation-negative MEN1 patients
    Visa övriga...
    2020 (Engelska)Ingår i: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 182, nr 1, s. 35-45Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    OBJECTIVE:Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant syndrome usually caused by loss-of-function mutations in the MEN1-gene. However, a minority of patients who fulfill the criteria for MEN1 are not found to harbor MEN1-mutations. Besides, some of these individuals, present with a subtly different phenotype suggestive of sporadic disease. The aim of the present study was to investigate the genetic architecture of mutation-negative MEN1. DESIGN:Fourteen patients with a clinical diagnosis (n=13) or suspicion (n=1) of MEN1 who had negative genetic screening of the MEN1 gene were included. METHODS:Constitutional DNA from the included patients, as well as tumor DNA from six of the patients, was subjected to whole genome sequencing. Constitutional variants were filtered against population databases and somatic variants were studied under a tumor-suppressor model. RESULTS:Three patients carried pathogenic variants (two splice-site variants, one missense variant) in MEN1 that had not been detected during routine clinical sequencing, one patient carried a pathogenic variant in CASR and one patient carried a gross deletion on chromosome 1q which included the CDC73 gene. Analysis of matched tumor DNA from six patients without mutations did not detect any recurrent genes fulfilling Knudson's two-hit model. CONCLUSION:These results highlight the possibility of germline mutations being missed in routine screening, the importance of considering phenocopies in atypical or mutation-negative cases. The absence of apparent disease-causing mutations suggests that a fraction of MEN1 mutation negative MEN1 cases may be due to the chance occurrence of several endocrine tumors in one patient.

    Nationell ämneskategori
    Endokrinologi och diabetes
    Identifikatorer
    urn:nbn:se:uu:diva-401244 (URN)10.1530/eje-19-0522 (DOI)000505970300008 ()31658439 (PubMedID)
    Forskningsfinansiär
    Cancerfonden
    Tillgänglig från: 2020-01-07 Skapad: 2020-01-07 Senast uppdaterad: 2020-10-19Bibliografiskt granskad
    4. Potential prognostic markers and candidate genetic drivers in small intestine neuroendocrine tumours
    Öppna denna publikation i ny flik eller fönster >>Potential prognostic markers and candidate genetic drivers in small intestine neuroendocrine tumours
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background

    Small intestinal neuroendocrine tumours (SI-NETs) are the most common tumour of the small intestine. The disease often has a favourable outcome with long survival even in the context of metastatic disease. However, some patients fare worse and succumb to the disease soon after diagnosis despite similar stage and grade. Molecular prognostic markers are lacking. The most common genetic aberration is loss of chromosome 18q, although the oncogenic mechanism of this is unknown. The only recurrently mutated gene is CDKN1B, which is mutated in 9% of cases.

    Aims

    To identify molecular derangements in SI-NETs and identify potential prognostic markers.

    Methods

    Forty tumour samples from thirty patients with unusually long or unusually short survival after diagnosis were subjected to whole genome sequencing. Twenty of the samples were also included for RNA Sequencing.

    Results

    In addition to mutations in CDKN1B we find rare variants in known cancer genes including NF1, MAX and SPEN. Unsupervised clustering based on gene expression resulted in two clusters with prognostic significance. We identify potential prognostic markers based on gene expression. Finally, we identify genes whose expression is affected by the most common copy number variations in these tumours, including SOCS6 on chromosome 18 and ATM on chromosome 11.

    Nyckelord
    neuroendocrine tumors, cancer, genetics, sequencing, gene expression
    Nationell ämneskategori
    Cancer och onkologi
    Forskningsämne
    Medicinsk vetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-423097 (URN)
    Tillgänglig från: 2020-10-19 Skapad: 2020-10-19 Senast uppdaterad: 2020-10-19
    Ladda ner fulltext (pdf)
    fulltext
    Ladda ner (jpg)
    presentationsbild
  • 48.
    Badhai, Jitendra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Ribosomal Proteins in Diamond-Blackfan Anemia: Insights into Failure of Ribosome Function2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Diamond-Blackfan anemia (DBA) is a severe congenital anemia characterized by a defect in red blood cell production. The disease is associated with growth retardation, malformations, a predisposition for malignant disease and heterozygous mutations in either of the ribosomal protein (RP) genes RPS7, RPS17, RPS19, RPS24, RPL5, RPL11 and RPL35a.

    In a cellular model for DBA, siRNA knock-down of RPS19 results in a relative decrease of other ribosomal (r) proteins belonging to the small subunit (RPS20, RPS21, RPS24) when compared to r-proteins from the large ribosomal subunit (RPL3, RPL9, RPL30, RPL38). RPS19 mutant cells from DBA patients show a similar and coordinated down-regulation of small subunit proteins. The mRNA levels of the small subunit r-proteins remain relatively unchanged. We also show that RPS19 has an extensive number of transcriptional start sites resulting in mRNAs of variable 5’UTR length. The short variants are translated more efficiently. Structural sequence variations in the 5’UTR of RPS19 found in DBA patients show a 20%-30% reduced translational activity when compared to normal transcripts.

    Primary fibroblast from DBA patients with truncating mutations in RPS19 or RPS24 showed specific cell cycle defects. RPS19 mutant fibroblasts accumulate in the G1 phase whereas the RPS24 mutant cells show a defect in G2/M phase. The G1 phase arrest is associated with a reduced level of phosphorylated retinoblastoma (Rb) protein, cyclin E and cdk2 whereas the G2/M phase defect is associated with increased levels of p21, cyclin E, cdk4 and cdk6.

    RPS19 interacts with PIM-1 kinase. We investigated the effects of targeted disruptions of both Rps19 and Pim-1 in mice. Double mutant (Rps19+/-, Pim-1-/-) mice have increased peripheral white- and red blood cell counts when compared to the wild-type mice (Rps19+/+, Pim-1+/+). Bone marrow cells in Rps19+/-, Pim-1-/- mice showed up-regulated levels of c-Myc and the anti-apoptotic factors Bcl2, Bcl-xl and Mcl-1 and reduced levels of the apoptotic factors Bak and Caspase 3 as well as the cell cycle regulator p21.

    In summary, this thesis clarifies several mechanisms in the pathogenesis of DBA. Mutations in RPS19 results in coordinated down-regulation of several small subunit r-proteins causing haploinsufficiency for the small ribosomal subunit. RPS19 have multiple transcriptional start sites and mutations in the RPS19 5’UTR found in DBA patients result in reduced translational activity. At the cellular level, mutations in RPS19 and RPS24 cause distinct cell cycle defects and reduced cell proliferation. Finally, PIM-1 kinase and RPS19 cooperates in the proliferation of myeloid cells.

    Delarbeten
    1. Posttranscriptional down-regulation of small ribosomal subunit proteinscorrelates with reduction of 18S rRNA in RPS19 deficiency
    Öppna denna publikation i ny flik eller fönster >>Posttranscriptional down-regulation of small ribosomal subunit proteinscorrelates with reduction of 18S rRNA in RPS19 deficiency
    Visa övriga...
    2009 (Engelska)Ingår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 583, nr 12, s. 2049-2053Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Ribosomal protein S19 (RPS19) is mutated in patients with Diamond-Blackfan anemia (DBA). We hypothesized that decreased levels of RPS19 lead to a coordinated down-regulation of other ribosomal (r-)proteins at the subunit level. We show that small interfering RNA (siRNA) knock-down of RPS19 results in a relative decrease of small subunit (SSU) r-proteins (S20, S21 and S24) when compared to large subunit (LSU) r-proteins (L3, L9, L30 and L38). This correlates with a relative decrease in 18S rRNA with respect to 28S rRNA. The r-protein mRNA levels remain relatively unchanged indicating a post transcriptional regulation of r-proteins at the level of subunit formation.

    Nyckelord
    Diamond-Blackfan anemia (DBA), Ribosomal protein 19, antibody, Haploinsufficiency, ribosome biogenesis
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-108108 (URN)10.1016/j.febslet.2009.05.023 (DOI)000267797800038 ()19454283 (PubMedID)
    Tillgänglig från: 2009-09-08 Skapad: 2009-09-08 Senast uppdaterad: 2022-01-28Bibliografiskt granskad
    2. Differential expression of RPS19 5’UTR variants implicated in Diamond-Blackfan anemia
    Öppna denna publikation i ny flik eller fönster >>Differential expression of RPS19 5’UTR variants implicated in Diamond-Blackfan anemia
    Visa övriga...
    2012 (Engelska)Artikel i tidskrift (Övrigt vetenskapligt) In press
    Abstract [en]

    Heterozygous mutations in the ribosomal protein (RP) S19 gene RPS19 are found in about 25% of patients with the congenital erythroblastopenia Diamond-Blackfan anemia (DBA). The RPS19 gene encodes a single RPS19 isoform from three known transcriptional start sites (TSS) with different 5’ untranslated region (UTR). The regulation of RPS19 expression is poorly understood as well as the significance of different 5’UTRs. A few rare sequence variants within the 5’UTR have also been reported in patients with DBA. We determined the transcriptional start sites (TSS) and the tissue distribution of variant 5’UTRs of RPS19. Twenty-nine novel TSS in K562 cells and testis were identified. We then analyzed the relative proportion of three selected 5’UTRs of different length on a panel of primary tissues. The shorter 5’UTR were most abundant in all tissues but with large variations in relative levels of shorter versus longer transcripts. To clarify the effect of different RPS19 5’UTRs on translation we designed and expressed constructs using three 5’UTRs of different length. The short 5’UTR(+35nt.) translate 4-6 folds more efficiently than the two longer variants with 5’UTRs of 382nt. and 467nt., respectively We also introduced DBA associated insertion (c.-149_-148insGCCA, c.-149_-148insAGCC ) and deletion (c.-144_-141delTTTC) variants in the 5’UTR. . Interestingly, the DBA associated 5’UTR sequence variants showed a 20-30% reduction in RPS19 levels when compared to the corresponding w.t. constructs. Our results indicate that the RPS19 gene has a broad range of TSS with tissue specific variations. We also show that sequence variants in the 5’UTR in some DBA patients reduce RPS19 expression with implications for the pathophysiology of the disease.

    Nyckelord
    Diamond-Blackfan anemai, 5'UTR, translation, RPS19, haploinsufficiency
    Nationell ämneskategori
    Medicinsk genetik
    Forskningsämne
    Klinisk genetik
    Identifikatorer
    urn:nbn:se:uu:diva-110063 (URN)
    Tillgänglig från: 2009-11-02 Skapad: 2009-11-02 Senast uppdaterad: 2022-01-28Bibliografiskt granskad
    3. Cooperative effect of ribosomal protein s19 and Pim-1 kinase on murine c-Myc expression and myeloid/erythroid cellularity
    Öppna denna publikation i ny flik eller fönster >>Cooperative effect of ribosomal protein s19 and Pim-1 kinase on murine c-Myc expression and myeloid/erythroid cellularity
    Visa övriga...
    2010 (Engelska)Ingår i: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 88, nr 1, s. 39-46Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Diamond Blackfan anemia (DBA) is a bone marrow failure syndrome associated with heterozygous mutations in the ribosomal protein S19 (RPS19) gene in a subgroup of patients. One of the interacting partners with RPS19 is the oncoprotein PIM-1 kinase. We intercrossed Rps19+/- and Pim-1-/- mice strains to study the effect from the disruption of both genes. The double mutant (Rps19+/-Pim-1-/-) mice display normal growth with increased peripheral white- and red blood cell counts when compared to the w.t. mice (Rps19+/+Pim-1+/+). Molecular analysis of bone marrow cells in Rps19+/-Pim-1-/- mice revealed up-regulated levels of c-Myc and the anti-apoptotic factors Bcl2, BclXL and Mcl-1. This is associated with a reduction of the apoptotic factors Bak and Caspase 3 as well as the cell cycle regulator p21. Our findings suggest that combined Rps19 insufficiency and Pim-1 deficiency promote murine myeloid cell growth through a deregulation of c-Myc and a simultaneous up-regulation of anti-apoptotic Bcl proteins.

    Ort, förlag, år, upplaga, sidor
    Springer, 2010
    Nyckelord
    ribosomal protein, Pim-1, RPS19, c-Myc
    Nationell ämneskategori
    Medicinsk genetik
    Forskningsämne
    Klinisk genetik
    Identifikatorer
    urn:nbn:se:uu:diva-110069 (URN)10.1007/s00109-009-0558-9 (DOI)000273668400006 ()19898770 (PubMedID)
    Tillgänglig från: 2009-11-02 Skapad: 2009-11-02 Senast uppdaterad: 2022-01-28Bibliografiskt granskad
    4. Ribosomal protein S19 and S24 insufficiency cause distinct cell cycle defects in Diamond-Blackfan anemia
    Öppna denna publikation i ny flik eller fönster >>Ribosomal protein S19 and S24 insufficiency cause distinct cell cycle defects in Diamond-Blackfan anemia
    Visa övriga...
    2009 (Engelska)Ingår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1792, nr 10, s. 1036-1042Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Diamond-Blackfan anemia (DBA) is a severe congenital anemia characterized by a specific decrease of erythroid precursors. The disease is also associated with growth retardation, congenital malformations, a predisposition for malignant disease and heterozygous mutations in either of the ribosomal protein (RP) genes RPS7, RPS17, RPS19, RPS24, RPL5, RPL11 and RPL35a. We show herein that primary fibroblasts from DBA patients with truncating mutations in RPS19 or in RPS24 have a marked reduction in proliferative capacity. Mutant fibroblasts are associated with extended cell cycles and normal levels of p53 when compared to w.t. cells. RPS19 mutant fibroblasts accumulate in the G1 phase, whereas the RPS24 mutant cells show an altered progression in the S phase resulting in reduced levels in the G2/M phase. RPS19 deficient cells exhibit reduced levels of Cyclin-E, CDK2 and retinoblastoma (Rb) protein supporting a cell cycle arrest in the G1 phase. In contrast, RPS24 deficient cells show increased levels of the cell cycle inhibitor p21 and a seemingly opposing increase in Cyclin-E, CDK4 and CDK6. In combination, our results show that RPS19 and RPS24 insufficient fibroblasts have an impaired growth caused by distinct blockages in the cell cycle. We suggest this proliferative constraint to be an important contributing mechanism for the complex extra-hematological features observed in DBA.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-110062 (URN)10.1016/j.bbadis.2009.08.002 (DOI)000271071600012 ()19689926 (PubMedID)
    Tillgänglig från: 2009-11-02 Skapad: 2009-11-02 Senast uppdaterad: 2022-01-28Bibliografiskt granskad
    Ladda ner fulltext (pdf)
    FULLTEXT01
  • 49.
    Badhai, Jitendra
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Fröjmark, Anne-Sophie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Gidlöf, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Differential expression of RPS19 5’UTR variants implicated in Diamond-Blackfan anemia2012Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Heterozygous mutations in the ribosomal protein (RP) S19 gene RPS19 are found in about 25% of patients with the congenital erythroblastopenia Diamond-Blackfan anemia (DBA). The RPS19 gene encodes a single RPS19 isoform from three known transcriptional start sites (TSS) with different 5’ untranslated region (UTR). The regulation of RPS19 expression is poorly understood as well as the significance of different 5’UTRs. A few rare sequence variants within the 5’UTR have also been reported in patients with DBA. We determined the transcriptional start sites (TSS) and the tissue distribution of variant 5’UTRs of RPS19. Twenty-nine novel TSS in K562 cells and testis were identified. We then analyzed the relative proportion of three selected 5’UTRs of different length on a panel of primary tissues. The shorter 5’UTR were most abundant in all tissues but with large variations in relative levels of shorter versus longer transcripts. To clarify the effect of different RPS19 5’UTRs on translation we designed and expressed constructs using three 5’UTRs of different length. The short 5’UTR(+35nt.) translate 4-6 folds more efficiently than the two longer variants with 5’UTRs of 382nt. and 467nt., respectively We also introduced DBA associated insertion (c.-149_-148insGCCA, c.-149_-148insAGCC ) and deletion (c.-144_-141delTTTC) variants in the 5’UTR. . Interestingly, the DBA associated 5’UTR sequence variants showed a 20-30% reduction in RPS19 levels when compared to the corresponding w.t. constructs. Our results indicate that the RPS19 gene has a broad range of TSS with tissue specific variations. We also show that sequence variants in the 5’UTR in some DBA patients reduce RPS19 expression with implications for the pathophysiology of the disease.

  • 50. Bahl, Aileen
    et al.
    Pöllänen, Eija
    Ismail, Khadeeja
    Sipilä, Sarianna
    Mikkola, Tuija M
    Berglund, Eva C
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lindqvist, Carl Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rantanen, Taina
    Kaprio, Jaakko
    Kovanen, Vuokko
    Ollikainen, Miina
    Hormone Replacement Therapy Associated White Blood Cell DNA Methylation and Gene Expression are Associated With Within-Pair Differences of Body Adiposity and Bone Mass2015Ingår i: Twin Research and Human Genetics, ISSN 1832-4274, E-ISSN 1839-2628, Vol. 18, nr 6, s. 647-661Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The loss of estrogen during menopause causes changes in the female body, with wide-ranging effects on health. Estrogen-containing hormone replacement therapy (HRT) leads to a relief of typical menopausal symptoms, benefits bone and muscle health, and is associated with tissue-specific gene expression profiles. As gene expression is controlled by epigenetic factors (including DNA methylation), many of which are environmentally sensitive, it is plausible that at least part of the HRT-associated gene expression is due to changes in DNA methylation profile. We investigated genome-wide DNA methylation and gene expression patterns of white blood cells (WBCs) and their associations with body composition, including muscle and bone measures of monozygotic (MZ) female twin pairs discordant for HRT. We identified 7,855 nominally significant differentially methylated regions (DMRs) associated with 4,044 genes. Of the genes with DMRs, five (ACBA1, CCL5, FASLG, PPP2R2B, and UHRF1) were also differentially expressed. All have been previously associated with HRT or estrogenic regulation, but not with HRT-associated DNA methylation. All five genes were associated with bone mineral content (BMC), and ABCA1, FASLG, and UHRF1 were also associated with body adiposity. Our study is the first to show that HRT associates with genome-wide DNA methylation alterations in WBCs. Moreover, we show that five differentially expressed genes with DMRs associate with clinical measures, including body fat percentage, lean body mass, bone mass, and blood lipids. Our results indicate that at least part of the known beneficial HRT effects on body composition and bone mass may be regulated by DNA methylation associated alterations in gene expression in circulating WBCs.

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