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  • 251.
    Reid, Sarah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Frodlund, Martina
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Sandling, Johanna K.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Jonsen, Andreas
    Lund Univ, Dept Clin Sci, Rheumatol, Lund, Sweden..
    Bengtsson, Christine
    Umea Univ, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden..
    Gunnarsson, Iva
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Bengtsson, Anders A.
    Lund Univ, Dept Clin Sci, Rheumatol, Lund, Sweden..
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden..
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sjowall, Christopher
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    High Genetic Risk Score Is Associated with Increased Organ Damage in SLE2017In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, no S10, article id 1638Article in journal (Other academic)
  • 252.
    Reisberg, Sulev
    et al.
    Univ Tartu, Inst Comp Sci, Tartu, Estonia;STACC, Tartu, Estonia;Quretec, Tartu, Estonia.
    Krebs, Kristi
    Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia;Univ Tartu, Inst Mol & Cell Biol, Tartu, Estonia.
    Lepamets, Maarja
    Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia;Univ Tartu, Inst Mol & Cell Biol, Tartu, Estonia.
    Kals, Mart
    Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia.
    Magi, Reedik
    Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia.
    Metsalu, Kristjan
    Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia.
    Lauschke, Volker M.
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Pharmacogenet, Stockholm, Sweden.
    Vilo, Jaak
    Univ Tartu, Inst Comp Sci, Tartu, Estonia;STACC, Tartu, Estonia;Quretec, Tartu, Estonia.
    Milani, Lili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia.
    Translating genotype data of 44,000 biobank participants into clinical pharmacogenetic recommendations: challenges and solutions2019In: Genetics in Medicine, ISSN 1098-3600, E-ISSN 1530-0366, Vol. 21, no 6, p. 1345-1354Article in journal (Refereed)
    Abstract [en]

    Purpose: Biomedical databases combining electronic medical records and phenotypic and genomic data constitute a powerful resource for the personalization of treatment. To leverage the wealth of information provided, algorithms are required that systematically translate the contained information into treatment recommendations based on existing genotype-phenotype associations. Methods: We developed and tested algorithms for translation of preexisting genotype data of over 44,000 participants of the Estonian biobank into pharmacogenetic recommendations. We compared the results obtained by genome sequencing, exome sequencing, and genotyping using microarrays, and evaluated the impact of pharmacogenetic reporting based on drug prescription statistics in the Nordic countries and Estonia. Results: Our most striking result was that the performance of genotyping arrays is similar to that of genome sequencing, whereas exome sequencing is not suitable for pharmacogenetic predictions. Interestingly, 99.8% of all assessed individuals had a genotype associated with increased risks to at least one medication, and thereby the implementation of pharmacogenetic recommendations based on genotyping affects at least 50 daily drug doses per 1000 inhabitants. Conclusion: We find that microarrays are a cost-effective solution for creating preemptive pharmacogenetic reports, and with slight modifications, existing databases can be applied for automated pharmacogenetic decision support for clinicians.

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  • 253.
    Roos, Leonie
    et al.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England.;MRC London Inst Med Sci, London, England.;Imperial Coll London, Inst Clin Sci, Fac Med, Du Cane Rd, London W12 0NN, England..
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bell, Christopher G.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England.;Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England.;Univ Southampton, Human Dev & Hlth Acad Unit, Inst Dev Sci, Southampton, Hants, England.;Univ Southampton, Fac Environm & Nat Sci, Ctr Biol Sci, Epigen Med, Southampton, Hants, England..
    Glass, Daniel
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Mangino, Massimo
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Spector, Tim D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Deloukas, Panos
    Queen Mary Univ London, William Harvey Res Inst, London, England..
    Bataille, Veronique
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Bell, Jordana T.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Higher Nevus Count Exhibits a Distinct DNA Methylation Signature in Healthy Human Skin: Implications for Melanoma2017In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 137, no 4, p. 910-920Article in journal (Refereed)
    Abstract [en]

    High nevus count is the strongest risk factor for melanoma, and although gene variants have been discovered for both traits, epigenetic variation is unexplored. We investigated 322 healthy human skin DNA methylomes associated with total body nevi count, incorporating genetic and transcriptomic variation. DNA methylation changes were identified at genes involved in melanocyte biology, such as RAF1 (P = 1.2x10(-6)) and CTC1 (region: P = 6.3 x 10(-4)), and other genes including ARRDC1 (P = 3.1 x 10(-7)). A subset exhibited coordinated methylation and transcription changes within the same biopsy. The total analysis was also enriched for melanoma-associated DNA methylation variation (P = 6.33 x 10(-6)). In addition, we show that skin DNA methylation is associated in cis with known genome-wide association study single nucleotide polymorphisms for nevus count, at PLA2G6 (P = 1.7 x 10(-49)) and NID1 (P = 6.4 x 10(-14)), as well as melanoma risk, including in or near MC1R, MX2, and TERT/CLPTM1L (P < 1 x 10(-10)). Our analysis using a uniquely large dataset comprising healthy skin DNA methylomes identified known and additional regulatory loci and pathways in nevi and melanoma biology. This integrative study improves our understanding of predisposition to nevi and their potential contribution to melanoma pathogenesis.

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  • 254.
    Roshanbin, Sahar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lindberg, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lekholm, Emilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Perland, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Eriksson, Mikaela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Åhlund, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Raine, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Histological characterization of orphan transporter MCT14 (SLC16A14) shows abundant expression in mouse CNS and kidney2016In: BMC Neuroscience, E-ISSN 1471-2202, Vol. 17, article id 43Article in journal (Refereed)
    Abstract [en]

    Background: MCT14 (SLC16A14) is an orphan member of the monocarboxylate transporter (MCT) family, also known as the SLC16 family of secondary active transmembrane transporters. Available expression data for this transporter is limited, and in this paper we aim to characterize MCT14 with respect to tissue distribution and cellular localization in mouse brain. Results: Using qPCR, we found that Slc16a14 mRNA was highly abundant in mouse kidney and moderately in central nervous system, testis, uterus and liver. Using immunohistochemistry and in situ hybridization, we determined that MCT14 was highly expressed in excitatory and inhibitory neurons as well as epithelial cells in the mouse brain. The expression was exclusively localized to the soma of neurons. Furthermore, we showed with our phylogenetic analysis that MCT14 most closely relate to the aromatic amino acid- and thyroid-hormone transporters MCT8 (SLC16A2) and MCT10 (SLC16A10), in addition to the carnitine transporter MCT9 (SLC16A9). Conclusions: We provide here the first histological mapping of MCT14 in the brain and our data are consistent with the hypothesis that MCT14 is a neuronal aromatic-amino-acid transporter.

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  • 255.
    Rönn, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Analysis of Nucleotide Variations in Non-human Primates2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Many of our closest relatives, the primates, are endangered and could be extinct in a near future. To increase the knowledge of non-human primate genomes, and at the same time acquire information on our own genomic evolution, studies using high-throughput technologies are applied, which raises the demand for large amounts of high quality DNA.

    In study I and II, we evaluated the multiple displacement amplification (MDA) technique, a whole genome amplification method, on a wide range of DNA sources, such as blood, hair and semen, by comparing MDA products to genomic DNA as templates for several commonly used genotyping methods. In general, the genotyping success rate from the MDA products was in concordance with the genomic DNA. The quality of sequences of the mitochondrial control region obtained from MDA products from blood and non-invasively collected semen samples was maintained. However, the readable sequence length was shorter for MDA products.

    Few studies have focused on the genetic variation in the nuclear genes of non-human primates. In study III, we discovered 23 new single nucleotide polymorphisms (SNPs) in the Y-chromosome of the chimpanzee. We designed a tag-microarray minisequencing assay for genotyping the SNPs together with 19 SNPs from the literature and 45 SNPs in the mitochondrial DNA. Using the microarray, we were able to analyze the population structure of wild-living chimpanzees.

    In study IV, we established 111 diagnostic nucleotide positions for primate genera determination. We used sequence alignments of the nuclear epsilon globin gene and apolipoprotein B gene to identify positions for determination on the infraorder and Catarrhini subfamily level, respectively, and sequence alignments of the mitochondrial 12S rRNA (MT-RNR1) to identify positions to distinguish between genera. We designed a microarray assay for immobilized minisequencing primers for genotyping these positions to aid in the forensic determination of an unknown sample.

    List of papers
    1. Multiple displacement amplification for generating an unlimited source of DNA for genotyping in nonhuman primate species
    Open this publication in new window or tab >>Multiple displacement amplification for generating an unlimited source of DNA for genotyping in nonhuman primate species
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    2006 (English)In: International journal of primatology, ISSN 0164-0291, E-ISSN 1573-8604, Vol. 27, no 4, p. 1145-1169Article in journal (Refereed) Published
    Abstract [en]

    We evaluated a whole genome amplification method-multiple displacement amplification (MDA)-as a means to conserve valuable nonhuman primate samples. We tested 148 samples from a variety of species and sample sources, including blood, tissue, cell-lines, plucked hair and noninvasively collected semen. To evaluate genotyping success and accuracy of MDA, we used routine genotyping methods, including short tandem repeat (STR) analysis, denaturing gradient gel electrophoresis (DGGE), Alu repeat analysis, direct sequencing, and nucleotide detection by tag-array minisequencing. We compared genotyping results from MDA products to genotypes generated from the original (non-MD amplified) DNA samples. All genotyping methods showed good results with the MDA products as a DNA template, and for some samples MDA improved genotyping success. We show that the MDA procedure has the potential to provide a long-lasting source of DNA for genetic studies, which would be highly valuable for the primate research field, in which genetic resources are limited and for other species in which similar sampling constraints apply.

    Keywords
    Alu-SINE, minisequencing, multiple displacement amplification, short tandem repeat, single nucleotide polymorphism
    National Category
    Medical and Health Sciences Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-95932 (URN)10.1007/s10764-006-9067-7 (DOI)000241400100012 ()
    Available from: 2007-05-10 Created: 2007-05-10 Last updated: 2017-12-14Bibliographically approved
    2. Sequence quality is maintained after multiple displacement amplification of non-invasively obtained macaque semen DNA
    Open this publication in new window or tab >>Sequence quality is maintained after multiple displacement amplification of non-invasively obtained macaque semen DNA
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    2006 In: Biotechnology Journal, ISSN 1860-7314, Vol. 1, no 4, p. 466-469Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-95933 (URN)
    Available from: 2007-05-10 Created: 2007-05-10Bibliographically approved
    3. A microarray system for Y chromosomal and mitochondrial single nucleotide polymorphism analysis in chimpanzee populations
    Open this publication in new window or tab >>A microarray system for Y chromosomal and mitochondrial single nucleotide polymorphism analysis in chimpanzee populations
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    2008 (English)In: Molecular Ecology Notes, ISSN 1471-8278, E-ISSN 1471-8286, Vol. 8, no 3, p. 529-539Article in journal (Refereed) Published
    Abstract [en]

    Chimpanzee populations are diminishing as a consequence of human activities, and as a result this species is now endangered. In the context of conservation programmes, genetic data can add vital information, for instance on the genetic diversity and structure of threatened populations. Single nucleotide polymorphisms (SNP) are biallelic markers that are widely used in human molecular studies and can be implemented in efficient microarray systems. This technology offers the potential of robust, multiplexed SNP genotyping at low reagent cost in other organisms than humans, but it is not commonly used yet in wild population studies. Here, we describe the characterization of new SNPs in Y-chromosomal intronic regions in chimpanzees and also identify SNPs from mitochondrial genes, with the aim of developing a microarray system that permits the simultaneous study of both paternal and maternal lineages. Our system consists of 42 SNPs for the Y chromosome and 45 SNPs for the mitochondrial genome. We demonstrate the applicability of this microarray in a captive population where genotypes accurately reflected its large pedigree. Two wild-living populations were also analysed and the results show that the microarray will be a useful tool alongside microsatellite markers, since it supplies complementary information about population structure and ecology. SNP genotyping using microarray technology, therefore, is a promising approach and may become an essential tool in conservation genetics to help in the management and study of captive and wild-living populations. Moreover, microarrays that combine SNPs from different genomic regions could replace microsatellite typing in the future.

    Keywords
    chimpanzee, conservation genetics, microarray, minisequencing, population genetics, sex-linked SNPs
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-110437 (URN)10.1111/j.1471-8286.2007.02000.x (DOI)000254810300007 ()
    Available from: 2009-11-16 Created: 2009-11-16 Last updated: 2017-12-12Bibliographically approved
    4. A microarray-system for forensic identification of primate species subject to bushmeat trade
    Open this publication in new window or tab >>A microarray-system for forensic identification of primate species subject to bushmeat trade
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    (English)Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-95935 (URN)10.3354/esr00191 (DOI)
    Available from: 2007-05-10 Created: 2007-05-10 Last updated: 2012-02-29
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    COVER01
  • 256.
    Rönn, Ann-Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Andrés, Olga
    Bruford, Michael W.
    Crouau-Roy, Brigitte
    Doxiadis, Gaby
    Domingo-Roura, Xavier
    Roeder, Amy D.
    Verschoor, Ernst
    Zischler, Hans
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Multiple displacement amplification for generating an unlimited source of DNA for genotyping in nonhuman primate species2006In: International journal of primatology, ISSN 0164-0291, E-ISSN 1573-8604, Vol. 27, no 4, p. 1145-1169Article in journal (Refereed)
    Abstract [en]

    We evaluated a whole genome amplification method-multiple displacement amplification (MDA)-as a means to conserve valuable nonhuman primate samples. We tested 148 samples from a variety of species and sample sources, including blood, tissue, cell-lines, plucked hair and noninvasively collected semen. To evaluate genotyping success and accuracy of MDA, we used routine genotyping methods, including short tandem repeat (STR) analysis, denaturing gradient gel electrophoresis (DGGE), Alu repeat analysis, direct sequencing, and nucleotide detection by tag-array minisequencing. We compared genotyping results from MDA products to genotypes generated from the original (non-MD amplified) DNA samples. All genotyping methods showed good results with the MDA products as a DNA template, and for some samples MDA improved genotyping success. We show that the MDA procedure has the potential to provide a long-lasting source of DNA for genetic studies, which would be highly valuable for the primate research field, in which genetic resources are limited and for other species in which similar sampling constraints apply.

  • 257.
    Rönn, Ann-Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Andrés, Olga
    López-Giráldez, Franscesc
    Johnsson-Glans, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Verschoor, Ernst
    Domingo-Roura, Xavier
    Bruford, Michael, W.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Bosch, Montserrat
    A microarray-system for forensic identification of primate species subject to bushmeat tradeManuscript (Other academic)
  • 258. Saetre, Peter
    et al.
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Wang, August
    Hansen, Thomas
    Rasmussen, Henrik B.
    Djurovic, Srdjan
    Melle, Ingrid
    Andreassen, Ole A.
    Werge, Thomas
    Agartz, Ingrid
    Hall, Håkan
    Terenius, Lars
    Jönsson, Erik G.
    The Tryptophan Hydroxylase 1 (TPH1) Gene, Schizophrenia Susceptibility, and Suicidal Behavior: A Multi-Centre Case-Control Study and Meta-Analysis2010In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, ISSN 1552-4841, Vol. 153B, no 2, p. 387-396Article in journal (Refereed)
    Abstract [en]

    Serotonin (5-hydroxytryptamin; 5-HT) alternations has since long been suspected in the pathophysiology of schizophrenia. Tryptophan hydroxylase (tryptophan 5-monooxygenase; TPH) is the rate-limiting enzyme in the biosynthesis of 5-HT, and sequence variation in intron 6 of the TPH1 gene has been associated with schizophrenia. The minor allele (A) of this polymorphism (A218C) is also more frequent in patients who have attempted suicide and individuals who died by suicide, than in healthy control individuals. In an attempt to replicate previous findings, five single nucleotide polymorphisms (SNPs) were genotyped in 837 Scandinavian schizophrenia patients and 1,473 controls. Three SNPs spanning intron 6 and 7, including the A218C and A779C polymorphisms, were associated with schizophrenia susceptibility (P = 0.019). However there were no differences in allele frequencies of these loci between affected individuals having attempted suicide at least once and patients with no history of suicide attempts (P=0.84). A systematic literature review and meta-analysis support the A218C polymorphism as a susceptibility locus for schizophrenia (odds ratio 1.17, 95% confidence interval 1.07-1.29). Association studies on suicide attempts are however conflicting (heterogeneity index I-2 = 0.54) and do not support the A218C/A779C polymorphisms being a susceptibility locus for suicidal behavior among individuals diagnosed with a psychiatric disorder (OR = 0.96 [0.80-1.16]). We conclude that the TPH1 A218/A779 locus increases the susceptibility of schizophrenia in Caucasian and Asian populations. In addition, the data at hand suggest that the locus contributes to the liability of psychiatric disorders characterized by elevated suicidal rates, rather than affecting suicidal behavior of individuals suffering from a psychiatric disorder.

  • 259.
    Sandling, Johanna K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Genetic Analyses of Multiple Sclerosis and Systemic Lupus Erythematosus: From Single Markers to Genome-Wide Data2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In autoimmune diseases an individual’s immune system becomes targeted at the body’s own healthy cells. The aim of this thesis was to identify genetic risk factors for the two autoimmune diseases multiple sclerosis (MS) and systemic lupus erythematosus (SLE). In Study I, we found that genetic variation in the interferon regulatory factor 5 gene (IRF5), previously shown to be associated with SLE, rheumatoid arthritis and inflammatory bowel diseases, was associated also with MS. An insertion/deletion polymorphism in the first intron of IRF5 is as a good functional candidate for this association. IRF5, together with the signal transducer and activator of transcription 4 gene (STAT4), are the most important genetic risk factors for SLE, outside the HLA region. In Study II we showed using a family-based study design that genetic variation in STAT4 is associated with SLE also in the Finnish population. In Study III, we investigated a STAT4 risk allele for SLE for its association with cardiovascular disease in SLE patients. The risk allele of STAT4 proved to be strongly associated with ischemic cerebrovascular disease and anti-phospholipid antibodies in SLE patients. A possible mechanism for this association is that the risk allele leads to increased production of pro-thrombotic anti-phospholipid antibodies, which in turn increases the risk for stroke. Both IRF5 and STAT4 are involved in signalling of the type I interferon system. In Study IV, we investigated 78 additional genes in this system for their association with SLE in a Swedish cohort. The most promising results were followed up in additional patients and controls from Sweden and the US. Two novel SLE genes were identified. In Study V a large follow-up of a genome-wide association study was performed. Five new SLE loci were identified: TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10. A number of genes previously shown to be associated with other autoimmune diseases were also tested for association with SLE. This analysis identified the type I interferon system gene IFIH1 as a novel SLE risk locus. These studies confirms the central role of the type I interferon system in SLE and further suggests common genetic risk factors in autoimmunity.

    List of papers
    1. Interferon Regulatory Factor 5 (IRF5) Gene Variants are Associated with Multiple Sclerosis in Three Distinct Populations
    Open this publication in new window or tab >>Interferon Regulatory Factor 5 (IRF5) Gene Variants are Associated with Multiple Sclerosis in Three Distinct Populations
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    2008 (English)In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 45, no 6, p. 362-369Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis (MS). METHODS: We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case-control cohorts from Spain and Sweden, and a set of MS trio families from Finland. RESULTS: Two single nucleotide polymorphism (SNPs) (rs4728142, rs3807306), and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with values of p<0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel. CONCLUSION: These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-16560 (URN)10.1136/jmg.2007.055012 (DOI)000256369500006 ()18285424 (PubMedID)
    Available from: 2008-05-28 Created: 2008-05-28 Last updated: 2022-09-15
    2. Variation in STAT4 is associated with systemic lupus erythematosus in a Finnish family cohort
    Open this publication in new window or tab >>Variation in STAT4 is associated with systemic lupus erythematosus in a Finnish family cohort
    Show others...
    2010 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 69, no 5, p. 883-886Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES:

    To investigate if 10 single nucleotide polymorphisms (SNPs) and haplotypes in the STAT4 gene, previously associated with SLE in a Swedish case-control cohort, also are associated with SLE risk in a Finnish SLE family cohort.

    METHOD:

    Genotyping was performed in 192 Finnish families, with 237 affected individuals and their healthy relatives, using the SNPstream genotyping system.

    RESULTS:

    TDT analysis provided the strongest signal of association for two linked SNPs; rs7582694 (P-value = 0.002, OR = 2.57) and rs10181656 (P-value = 0.001, OR = 2.53). We further performed haplotype association analysis using a sliding window approach which showed that the strongest association signal originates from SNPs in intron 3 of STAT4.

    CONCLUSION:

    Our results provide evidence that the main association signal for STAT4 with SLE previously reported in Caucasians is the same in the Finnish population. This is the first study that confirms the association of STAT4 with SLE in a family cohort.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-117769 (URN)10.1136/ard.2009.112284 (DOI)000276982300021 ()19717398 (PubMedID)
    Note

    De två första författarna delar förstaförfattarskapet

    Available from: 2010-02-22 Created: 2010-02-22 Last updated: 2017-12-12Bibliographically approved
    3. A STAT4 risk allele is associated with ischaemic cerebrovascular events and anti-phospholipid antibodies in systemic lupus erythematosus
    Open this publication in new window or tab >>A STAT4 risk allele is associated with ischaemic cerebrovascular events and anti-phospholipid antibodies in systemic lupus erythematosus
    Show others...
    2010 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 69, no 5, p. 834-840Article in journal (Refereed) Published
    Abstract [en]

    Objective

    To investigate whether the risk allele for systemic lupus erythematosus (SLE) in the signal transducer and activator of transcription factor 4 (STAT4) gene, defined by the single nucleotide polymorphism (SNP) rs10181656(G), is associated with vascular events and/or presence of prothrombotic anti-phospholipid antibodies (aPL) in patients with SLE.

    Methods

    Two independent groups of unrelated patients with SLE of Swedish ethnicity (n=424 and 154) were genotyped, and occurrence of previous manifestations of ischaemic heart disease (IHD), ischaemic cerebrovascular disease (ICVD) and venous thromboembolic events (VTE) was tabulated. aPL values were measured by ELISA. Matched controls (n=492 and 194) were genotyped.

    Results

    The STAT4 risk allele was more frequent in patients with SLE with previous arterial events (combined OR (ORc)=1.5, 95% CI 1.1 to 2.0) compared to patients without such events. The association was mainly attributable to an accumulation of the risk allele among patients with ICVD (ORc=2.3, CI 1.6 to 3.3). There was no association with IHD or VTE. The presence of two or more aPLs was associated with the risk allele (ORc=1.6, 95% CI 1.2 to 2.0). In multivariable-adjusted logistic regression analyses treatment for hypertension, at least one STAT4 risk allele, older age, IgG anti-cardiolipin antibodies and longer SLE duration remained independently associated with previous ICVD (p≤0.02 for all).

    Conclusion

    Patients with SLE with the STAT4 risk allele had a strikingly increased risk of ICVD, comparable in magnitude to that of hypertension. The results imply that a genetic predisposition is an important and previously unrecognised risk factor for ICVD in SLE, and that aPLs may be one underlying mechanism.

    Keywords
    STAT4, lupus, SLE, stroke
    National Category
    Medical and Health Sciences
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:uu:diva-117768 (URN)10.1136/ard.2009.115535 (DOI)000276982300011 ()19762360 (PubMedID)
    Available from: 2010-02-22 Created: 2010-02-22 Last updated: 2017-12-12Bibliographically approved
    4. Dissection of genes in the type I interferon pathway reveals two novel risk loci for SLE
    Open this publication in new window or tab >>Dissection of genes in the type I interferon pathway reveals two novel risk loci for SLE
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    2012 (English)Article in journal (Refereed) Submitted
    National Category
    Rheumatology and Autoimmunity
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:uu:diva-117774 (URN)
    Available from: 2010-03-26 Created: 2010-02-22 Last updated: 2012-02-16Bibliographically approved
    5. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus
    Open this publication in new window or tab >>A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus
    Show others...
    2009 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 41, no 11, p. 1228-1233Article in journal (Refereed) Published
    Abstract [en]

    Genome-wide association studies have recently identified at least 15 susceptibility loci for systemic lupus erythematosus (SLE). To confirm additional risk loci, we selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P < 0.05) in a genome-wide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This replication effort identified five new SLE susceptibility loci (P < 5 x 10(-8)): TNIP1 (odds ratio (OR) = 1.27), PRDM1 (OR = 1.20), JAZF1 (OR = 1.20), UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19). We identified 21 additional candidate loci with P< or = 1 x 10(-5). A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 x 10(-3)) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3. These results expand the number of confirmed and candidate SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis.

    Keywords
    type I IFN system, autoimmunity, lupus, SLE, risk genes
    National Category
    Medical and Health Sciences
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:uu:diva-117767 (URN)10.1038/ng.468 (DOI)000271247600016 ()19838195 (PubMedID)
    Note

    De två första författarna delar förstaförfattarskapet

    Available from: 2010-02-22 Created: 2010-02-22 Last updated: 2017-12-12Bibliographically approved
    Download full text (pdf)
    FULLTEXT01
  • 260.
    Sandling, Johanna K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Garnier, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Sigurdsson, Snaevar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Wang, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gunnarsson, Iva
    Svenungsson, Elisabet
    Padyukov, Leonid
    Sturfelt, Gunnar
    Jönsen, Andreas
    Bengtsson, Anders A.
    Truedsson, Lennart
    Eriksson, Catharina
    Rantapää-Dahlqvist, Solbritt
    Mälarstig, Anders
    Strawbridge, Rona J.
    Hamsten, Anders
    Criswell, Lindsey A.
    Graham, Robert R.
    Behrens, Timothy W.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Alm, Gunnar
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    A candidate gene study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SLE2011In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 19, no 4, p. 479-484Article in journal (Refereed)
    Abstract [en]

    Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease in which the type I interferon pathway has a crucial role. We have previously shown that three genes in this pathway, IRF5, TYK2 and STAT4, are strongly associated with risk for SLE. Here, we investigated 78 genes involved in the type I interferon pathway to identify additional SLE susceptibility loci. First, we genotyped 896 single-nucleotide polymorphisms in these 78 genes and 14 other candidate genes in 482 Swedish SLE patients and 536 controls. Genes with P<0.01 in the initial screen were then followed up in 344 additional Swedish patients and 1299 controls. SNPs in the IKBKE, TANK, STAT1, IL8 and TRAF6 genes gave nominal signals of association with SLE in this extended Swedish cohort. To replicate these findings we extracted data from a genomewide association study on SLE performed in a US cohort. Combined analysis of the Swedish and US data, comprising a total of 2136 cases and 9694 controls, implicates IKBKE and IL8 as SLE susceptibility loci (P(meta)=0.00010 and P(meta)=0.00040, respectively). STAT1 was also associated with SLE in this cohort (P(meta)=3.3 × 10(-5)), but this association signal appears to be dependent of that previously reported for the neighbouring STAT4 gene. Our study suggests additional genes from the type I interferon system in SLE, and highlights genes in this pathway for further functional analysis.

  • 261.
    Sandling, Johanna K
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Garnier, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Sigurdsson, Snaevar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Wang, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gunnarsson, Iva
    Svenungsson, Elisabeth
    Padyukov, Leonid
    Sturfelt, Gunnar
    Jönsen, Andreas
    Bengtsson, Anders A
    Truedsson, Lennart
    Eriksson, Catharina
    Rantapää-Dahlqvist, Solbritt
    Mälarstig, Anders
    Strawbridge, Rona J
    Hamsten, Anders
    Criswell, Lindsey A
    Graham, Robert R
    Behrens, Timothy W
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Alm, Gunnar
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Dissection of genes in the type I interferon pathway reveals two novel risk loci for SLE2012Article in journal (Refereed)
  • 262.
    Sandling, Johanna K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Imgenberg-Kreuz, Juliana
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Carlsson Almlöf, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Padyukov, L.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Gunnarsson, I.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Svenungsson, E.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Sjowall, C.
    Linkoping Univ, Dept Clin & Expt Med, Rheumatol AIR, Linkoping, Sweden..
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genome-wide analysis of DNA methylation in systemic lupus erythematosus2015In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 33, no 3, p. S74-S74Article in journal (Other academic)
  • 263.
    Sandling, Johanna K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Pucholt, Pascal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Hultin-Rosenberg, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Farias, Fabiana H. G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Washington Univ, Dept Psychiat, St Louis, MO 63110 USA..
    Kozyrev, Sergey V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Bianchi, Matteo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Padyukov, Leonid
    Karolinska Inst, Dept Med, Div Rheumatol, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Bengtsson, Christine
    Umeå Univ, Dept Publ Hlth & Clin Med Rheumatol, Umeå, Sweden..
    Jonsson, Roland
    Univ Bergen, Dept Clin Sci, Broegelmann Res Lab, Bergen, Norway..
    Omdal, Roald
    Univ Bergen, Dept Clin Sci, Broegelmann Res Lab, Bergen, Norway.;Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway..
    Lie, Benedicte A.
    Univ Oslo, Dept Med Genet, Oslo, Norway..
    Massarenti, Laura
    Copenhagen Univ Hosp, Rigshosp, Ctr Rheumatol & Spine Dis, Inst Inflammat Res, Copenhagen, Denmark..
    Steffensen, Rudi
    Aalborg Univ, Dept Clin Immunol, Aalborg, Denmark..
    Jakobsen, Marianne A.
    Odense Univ Hosp, Dept Clin Immunol, Odense, Denmark..
    Lillevang, Soren T.
    Odense Univ Hosp, Dept Clin Immunol, Odense, Denmark..
    Lerang, Karoline
    Oslo Univ Hosp, Dept Rheumatol, Oslo, Norway..
    Molberg, Oyvind
    Oslo Univ Hosp, Dept Rheumatol, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Voss, Anne
    Odense Univ Hosp, Dept Rheumatol, Odense, Denmark..
    Troldborg, Anne
    Aarhus Univ Hosp, Dept Rheumatol, Aarhus, Denmark.;Aarhus Univ, Inst Clin Med, Aarhus, Denmark..
    Jacobsen, Soren
    Copenhagen Univ Hosp, Rigshosp, Ctr Rheumatol & Spine Dis, Copenhagen, Denmark.;Univ Copenhagen, Inst Clin Med, Copenhagen, Denmark..
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jonsen, Andreas
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Rheumatol, Lund, Sweden..
    Gunnarsson, Iva
    Karolinska Inst, Dept Med, Div Rheumatol, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Svenungsson, Elisabet
    Karolinska Inst, Dept Med, Div Rheumatol, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Rantapaa-Dahlqvist, Solbritt
    Umeå Univ, Dept Publ Hlth & Clin Med Rheumatol, Umeå, Sweden..
    Bengtsson, Anders A.
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Rheumatol, Lund, Sweden..
    Sjowall, Christopher
    Linköping Univ, Dept Biomed & Clin Sci, Div Inflammat & Infect, Linköping, Sweden..
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing2021In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 80, no 1, p. 109-117Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease with extensive heterogeneity in disease presentation between patients, which is likely due to an underlying molecular diversity. Here, we aimed at elucidating the genetic aetiology of SLE from the immunity pathway level to the single variant level, and stratify patients with SLE into distinguishable molecular subgroups, which could inform treatment choices in SLE.

    METHODS: We undertook a pathway-centred approach, using sequencing of immunological pathway genes. Altogether 1832 candidate genes were analysed in 958 Swedish patients with SLE and 1026 healthy individuals. Aggregate and single variant association testing was performed, and we generated pathway polygenic risk scores (PRS).

    RESULTS: We identified two main independent pathways involved in SLE susceptibility: T lymphocyte differentiation and innate immunity, characterised by HLA and interferon, respectively. Pathway PRS defined pathways in individual patients, who on average were positive for seven pathways. We found that SLE organ damage was more pronounced in patients positive for the T or B cell receptor signalling pathways. Further, pathway PRS-based clustering allowed stratification of patients into four groups with different risk score profiles. Studying sets of genes with priors for involvement in SLE, we observed an aggregate common variant contribution to SLE at genes previously reported for monogenic SLE as well as at interferonopathy genes.

    CONCLUSIONS: Our results show that pathway risk scores have the potential to stratify patients with SLE beyond clinical manifestations into molecular subsets, which may have implications for clinical follow-up and therapy selection.

    Download full text (pdf)
    FULLTEXT01
  • 264.
    Sarkisyan, Daniil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Schumann, Gunter
    Kings Coll London, Inst Psychiat, London, England..
    Yakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Damaged reward areas in human alcoholics: neuronal proportion decline and astrocyte activation2017In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 133, no 3, p. 485-487Article in journal (Refereed)
  • 265.
    Satizabal, Claudia L.
    et al.
    UT Hlth San Antonio, Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX 78229 USA;UT Hlth San Antonio, Dept Populat Hlth Sci, San Antonio, TX 78229 USA;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.
    Adams, Hieab H. H.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands;Erasmus MC, Dept Clin Genet, 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.
    White, Charles C.
    Broad Inst, Cell Circuits Program, Cambridge, MA USA;Columbia Univ, Dept Neurol, Med Ctr, Ctr Translat & Computat Neuroimmunol, New York, NY USA.
    Knol, Maria J.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    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 27515 USA;Univ N Carolina, UNC Neurosci Ctr, Chapel Hill, NC 27515 USA.
    Scholz, Markus
    Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany;Univ Leipzig, LIFE Leipzig Res Ctr Civilizat Dis, Leipzig, Germany.
    Sargurupremraj, Muralidharan
    Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, Team Vintage, INSERM,UMR 1219, Bordeaux, France.
    Jahanshad, Neda
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA.
    Roshchupkin, Gennady, V
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands;Erasmus MC, Dept Med Informat, Rotterdam, Netherlands.
    Smith, Albert, V
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA;Univ Iceland, Fac Med, Reykjavik, Iceland;Iceland Heart Assoc, Kopavogur, Iceland.
    Bis, Joshua C.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA.
    Jian, Xueqiu
    Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Houston, TX 77030 USA.
    Luciano, Michelle
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Dept Psychol, Edinburgh, Midlothian, Scotland.
    Hofer, Edith
    Med Univ Graz, Dept Neurol, Clin Div Neurogeriatr, Graz, Austria;Med Univ Graz, Inst Med Informat Stat & Documentat, Graz, Austria.
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany.
    van der Lee, Sven J.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    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.
    Yanek, Lisa R.
    Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Program, Baltimore, MD 21205 USA.
    Lee, Tom, V
    Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA.
    Li, Shuo
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA.
    Hu, Yanhui
    Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.
    Koh, Jia Yu
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.
    Eicher, John D.
    NHLBI, Div Intramural Res, Populat Sci Branch, Framingham, MA USA.
    Desrivieres, Sylvane
    Kings Coll London, MRC SGDP Ctr, Inst Psychiat Psychol & Neurosci, London, England.
    Arias-Vasquez, Alejandro
    Radboud Univ Nijmegen, Dept Cognit Neurosci, Med Ctr, Nijmegen, Netherlands;Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Nijmegen, Netherlands;Radboud Univ Nijmegen, Dept Psychiat, Med Ctr, Nijmegen, Netherlands;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.
    Chauhan, Ganesh
    Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, Team Vintage, INSERM,UMR 1219, Bordeaux, France;Indian Inst Sci, Ctr Brain Res, Bangalore, Karnataka, India.
    Athanasiu, Lavinia
    Oslo Univ Hosp, Div Mental Hlth & Addict, CoE NORMENT, Oslo, Norway;Univ Oslo, Inst Clin Med, CoE NORMENT, Oslo, Norway.
    Rentera, Miguel E.
    QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Brisbane, Qld, Australia.
    Kim, Sungeun
    Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA;Indiana Univ Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN 46202 USA;Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA.
    Hoehn, David
    Max Planck Inst Psychiat, Munich, Germany.
    Armstrong, Nicola J.
    Murdoch Univ, Math & Stat, Perth, WA, Australia.
    Chen, Qiang
    Lieber Inst Brain Dev, Baltimore, MD USA.
    Holmes, Avram J.
    Yale Univ, Dept Psychol, New Haven, CT USA;Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.
    den Braber, Anouk
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands;Vrije Univ, Netherlands Twin Register, Amsterdam, Netherlands;Amsterdam Neurosci, Amsterdam, Netherlands;Vrije Univ Amsterdam, Dept Neurol, Amsterdam UMC, Amsterdam Neurosci,Alzheimer Ctr Amsterdam, Amsterdam, Netherlands.
    Kloszewska, Iwona
    Med Univ Lodz, Lodz, Poland.
    Andersson, Micael
    Umea Univ, Dept Integrat Med Biol, Umea, Sweden;Umea Univ, Umea Ctr Funct Brain Imaging UFBI, Umea, Sweden.
    Espeseth, Thomas
    Oslo Univ Hosp, Div Mental Hlth & Addict, CoE NORMENT, Oslo, Norway;Univ Oslo, Dept Psychol, Oslo, Norway.
    Grimm, Oliver
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Mannheim, Germany.
    Abramovic, Lucija
    Univ Utrecht, Univ Med Ctr Utrecht, UMC Brain Ctr, Dept Psychiat, Utrecht, Netherlands.
    Alhusaini, Saud
    Royal Coll Surgeons Ireland, Dublin, Ireland;Yale Sch Med, Dept Neurol, New Haven, CT USA.
    Milaneschi, Yuri
    Vrije Univ Amsterdam, Dept Psychiat, Amsterdam Neurosci, Med Ctr, 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, Bern, Switzerland.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ehrlich, Stefan
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA;Tech Univ Dresden, Div Psychol & Social Med & Dev Neurosci, Fac Med, Dresden, Germany;Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA.
    Roiz-Santianez, Roberto
    Univ Cantabria IDIVAL, Univ Hosp Marques de Valdecilla, Sch Med, Dept Psychiat, Santander, Spain;Univ Cantabria IDIVAL, Univ Hosp Marques de Valdecilla, Sch Med, Dept Med, Santander, Spain;Ctr Invest Biomed Red Salud Mental, Santander, Spain.
    Kraemer, Bernd
    Heidelberg Univ, Dept Gen Psychiat, Sect Expt Psychopathol & Neuroimaging, Heidelberg, Germany.
    Haberg, Asta K.
    Norwegian Univ Sci & Technol, Fac Med, Dept Neurosci, Trondheim, Norway;Trondheim Reg & Univ Hosp, St Olavs Hosp, Dept Radiol, Trondheim, Norway.
    Jones, Hannah J.
    Univ Bristol, Ctr Acad Mental Hlth, Bristol Med Sch, Populat Hlth Sci, Bristol, Avon, England;Univ Bristol, Bristol Med Sch, MRC Integrat Epidemiol Unit, Bristol, Avon, England;Univ Hosp Bristol NHS Fdn Trust, NIHR Bristol Biomed Res Ctr, Bristol, Avon, England;Univ Bristol, Bristol, Avon, England.
    Pike, G. Bruce
    Univ Calgary, Dept Radiol, Calgary, AB, Canada;Univ Calgary, Dept Clin Neurosci, Calgary, AB, Canada.
    Stein, Dan J.
    Univ Cape Town, Dept Psychiat & Mental Hlth, Cape Town, South Africa;South African Med Res Council, Unit Risk & Resilience Mental Disorders, Cape Town, South Africa.
    Stevens, Allison
    Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA.
    Bralten, Janita
    Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Nijmegen, Netherlands;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.
    Vernooij, Meike W.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands.
    Harris, Tamara B.
    NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, NIH, Bethesda, MD 20892 USA.
    Filippi, Irina
    Paris Saclay Univ, INSERM, Res Unit Neuroimaging & Psychiat 1000, Gif Sur Yvette, France;Paris Descartes Univ, DIGITEO Labs, Gif Sur Yvette, France.
    Witte, A. Veronica
    Max Planck Inst Human Cognit & Brain Sci, Dept Neurol, Leipzig, Germany;Univ Leipzig, Fac Med, CRC Obes Mech 1052, Leipzig, Germany.
    Guadalupe, Tulio
    Int Max Planck Res Sch Language Sci, Nijmegen, Netherlands;Max Planck Inst Psycholinguist, Language & Genet Dept, Nijmegen, Netherlands.
    Wittfeld, Katharina
    Univ Med Greifswald, Dept Psychiat, Greifswald, Germany;German Ctr Neurodegenerat Dis, Greifswald, Germany.
    Mosley, Thomas H.
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA.
    Becker, James T.
    Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA;Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA;Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA.
    Doan, Nhat Trung
    Hagenaars, Saskia P.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Dept Psychol, Edinburgh, Midlothian, Scotland.
    Saba, Yasaman
    Med Univ Graz, Gottfried Schatz Res Ctr Cell Signaling Metab & A, Res Unit Genet Epidemiol, Graz, Austria.
    Cuellar-Partida, Gabriel
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia.
    Amin, Najaf
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    Hilal, Saima
    Natl Univ Singapore, Dept Pharmacol, Singapore, Singapore;Natl Univ Hlth Syst, Memory Aging & Cognit Ctr, Singapore, Singapore.
    Nho, Kwangsik
    Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA;Indiana Univ Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN 46202 USA;Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA.
    Mirza-Schreiber, Nazanin
    Max Planck Inst Psychiat, Munich, Germany;German Res Ctr Environm Hlth, Inst Neurogen, Helmholtz Zentrum Munchen, Neuherberg, Germany.
    Arfanakis, Konstantinos
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA;IIT, Dept Biomed Engn, Chicago, IL 60616 USA;Rush Univ, Med Ctr, Dept Diagnost Radiol & Nucl Med, Chicago, IL 60612 USA.
    Becker, Diane M.
    Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Program, Baltimore, MD 21205 USA.
    Ames, David
    Univ Melbourne, Acad Unit Psychiat Old Age, Melbourne, Vic, Australia;Royal Melbourne Hosp, Natl Ageing Res Inst, Melbourne, Vic, Australia.
    Goldman, Aaron L.
    Lieber Inst Brain Dev, Baltimore, MD USA.
    Lee, Phil H.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA;Harvard Med Sch, Boston, MA 02115 USA;Harvard Med Sch, Lurie Ctr Autism, Massachusetts Gen Hosp, Lexington, MA USA;Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Genom Med, Boston, MA 02114 USA;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Boston, MA USA.
    Boomsma, Dorret, I
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands;Vrije Univ, Netherlands Twin Register, Amsterdam, Netherlands;Amsterdam Neurosci, Amsterdam, Netherlands;Vrije Univ Amsterdam Med Ctr, Amsterdam Publ Hlth Res Inst, Amsterdam, Netherlands.
    Lovestone, Simon
    Univ Oxford, Dept Psychiat, Oxford, England;Kings Coll London, NIHR Dementia Biomed Res Unit, London, England.
    Giddaluru, Sudheer
    Univ Bergen, Dept Clin Sci, NORMENT, Bergen, Norway;Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway.
    Le Hellard, Stephanie
    Univ Bergen, Dept Clin Sci, NORMENT, Bergen, Norway;Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway.
    Mattheisen, Manuel
    Aarhus Univ, Ctr Integrated Sequencing, Aarhus, Denmark;Aarhus Univ, Dept Biomed, Aarhus, Denmark;Lundbeck Fdn Initiat Integrat Psychiat Res iPSYCH, Aarhus, Denmark;Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden;Stockholm Cty Council, Stockholm Hlth Care Serv, Stockholm, Sweden.
    Bohlken, Marc M.
    Univ Utrecht, Univ Med Ctr Utrecht, UMC Brain Ctr, Dept Psychiat, Utrecht, Netherlands.
    Kasperaviciute, Dalia
    UCL Queen Sq Inst Neurol, London, England;Chalfont Ctr Epilepsy, Gerrards Cross, Bucks, England.
    Schmaal, Lianne
    Univ Melbourne, Ctr Youth Mental Hlth, Melbourne, Vic, Australia;Orygen, Natl Ctr Excellence Youth Mental Hlth, Melbourne, Vic, Australia.
    Lawrie, Stephen M.
    Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland.
    Agartz, Ingrid
    Univ Oslo, Inst Clin Med, CoE NORMENT, Oslo, Norway;Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden;Diakonhjemmet Hosp, Dept Res & Dev, Oslo, Norway.
    Walton, Esther
    Tech Univ Dresden, Div Psychol & Social Med & Dev Neurosci, Fac Med, Dresden, Germany;Univ Bath, Dept Psychol, Bath, Avon, England.
    Tordesillas-Gutierrez, Diana
    Ctr Invest Biomed Red Salud Mental, Santander, Spain;Valdecilla Biomed Res Inst IDIVAL, Neuroimaging Unit, Technol Facil, Santander, Spain.
    Davies, Gareth E.
    Avera Inst Human Genet, Sioux Falls, SD USA.
    Shin, Jean
    Univ Toronto, Lospital Sick Children, Toronto, ON, Canada.
    Ipser, Jonathan C.
    Univ Cape Town, Dept Psychiat & Mental Hlth, Cape Town, South Africa.
    Vinke, Louis N.
    Boston Univ, Ctr Syst Neurosci, Boston, MA 02215 USA.
    Hoogman, Martine
    Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Nijmegen, Netherlands;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.
    Jia, Tianye
    Kings Coll London, MRC SGDP Ctr, Inst Psychiat Psychol & Neurosci, London, England.
    Burkhardt, Ralph
    Univ Leipzig, LIFE Leipzig Res Ctr Civilizat Dis, Leipzig, Germany;Univ Hosp Regensburg, Inst Clin Chem & Lab Med, Regensburg, Germany.
    Klein, Marieke
    Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Nijmegen, Netherlands;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.
    Crivello, Fabrice
    Univ Bordeaux, Neurodegeneratives Dis Inst, CNRS UMR 5293, Bordeaux, France.
    Janowitz, Deborah
    Univ Med Greifswald, Dept Psychiat, Greifswald, Germany.
    Carmichael, Owen
    Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA.
    Haukvik, Unn K.
    Oslo Univ Hosp, Div Mental Hlth & Addict, CoE NORMENT, Oslo, Norway;Univ Oslo, Inst Clin Med, Dept Adult Psychiat, Oslo, Norway.
    Aribisala, Benjamin S.
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland;Lagos State Univ, Dept Comp Sci, Ojo, Nigeria.
    Schmidt, Helena
    Med Univ Graz, Gottfried Schatz Res Ctr Cell Signaling Metab & A, Res Unit Genet Epidemiol, Graz, Austria.
    Strike, Lachlan T.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia;Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.
    Cheng, Ching-Yu
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore;Duke NUS Med Sch, Ophthalmol & Visual Sci Acad Clin Program Eye ACP, Singapore, Singapore.
    Risacher, Shannon L.
    Indiana Univ Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN 46202 USA;Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA.
    Puetz, Benno
    Max Planck Inst Psychiat, Munich, Germany.
    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.
    Assareh, Amelia A.
    Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW, Australia.
    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.
    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.
    Mecocci, Patrizia
    Univ Perugia, Dept Med, Sect Gerontol & Geriatr, Perugia, Italy.
    Dale, Anders M.
    Univ Calif San Diego, Ctr Multimodal Imaging & Genet, San Diego, CA 92103 USA;Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92103 USA;Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA;Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA;Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA.
    Cichon, Sven
    Univ Basel, Dept Biomed, Div Med Genet, Basel, Switzerland;Univ Bonn, Inst Human Genet, Bonn, Germany;Res Ctr Julich, Inst Neurosci & Med Struct & Funct Org Brain INM, Julich, Germany.
    Boks, Marco P.
    Univ Utrecht, Univ Med Ctr Utrecht, UMC Brain Ctr, Dept Psychiat, Utrecht, Netherlands.
    Matarin, Mar
    UCL Queen Sq Inst Neurol, London, England;UCL Inst Neurol, Reta Lila Weston Inst, London, England;UCL Inst Neurol, Dept Mol Neurosci, London, England.
    Penninx, Brenda W. J. H.
    Vrije Univ Amsterdam, Dept Psychiat, Amsterdam Neurosci, Med Ctr, Amsterdam, Netherlands.
    Calhoun, Vince D.
    Univ New Mexico, Dept ECE, Albuquerque, NM 87131 USA;Mind Res Network, Albuquerque, NM USA;LBERI, Albuquerque, NM USA;Georgia State Univ, Triinst Ctr Translat Res Neuroimaging & Data Sci, Atlanta, GA 30303 USA.
    Chakravarty, M. Mallar
    Douglas Mental Hlth Univ Inst, Cerebral Imaging Ctr, Montreal, PQ, Canada;McGill Univ, Dept Psychiat, Montreal, PQ, Canada;McGill Univ, Dept Biol & Biomed Engn, Montreal, PQ, Canada.
    Marquand, Andre F.
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands;Radboud Univ Nijmegen, Donders Ctr Cognit Neuroimaging, Nijmegen, Netherlands.
    Macare, Christine
    Kings Coll London, MRC SGDP Ctr, Inst Psychiat Psychol & Neurosci, London, England.
    Masouleh, Shahrzad Kharabian
    Max Planck Inst Human Cognit & Brain Sci, Dept Neurol, Leipzig, Germany;Res Ctr Julich, Inst Neurosci & Med Brain & Behav INM 7, Julich, Germany.
    Oosterlaan, Jaap
    Vrije Univ Amsterdam, Clin Neuropsychol Sect, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam UMC, Amsterdam Reprod & Dev, Emma Neurosci Grp,Dept Pediat,Emma Childrens Hosp, Amsterdam, Netherlands.
    Amouyel, Philippe
    Univ Lille, RID AGE Risk Factors & Mol Determinants Aging Rel, LabEx DISTALZ U1167, Lille, France;Inserm U1167, Lille, France;Ctr Hosp Univ Lille, Lille, France;Inst Pasteur, Lille, France.
    Hegenscheid, Katrin
    Univ Med Greifswald, Inst Diagnost Radiol & Neuroradiol, Greifswald, Germany.
    Rotter, Jerome, I
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst & Pediat, Torrance, CA 90509 USA.
    Schork, Andrew J.
    Mental Hlth Ctr Sct Hans, Inst Biol Psychiat, Roskilde, Denmark;Translat Genom Res Inst, Neurogen Div, Phoenix, AZ USA.
    Liewald, David C. M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Dept Psychol, Edinburgh, Midlothian, Scotland.
    de Zubicaray, Greig, I
    Queensland Univ Technol, Fac Hlth, Brisbane, Qld, Australia;Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia.
    Wong, Tien Yin
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore;Duke NUS Med Sch, Acad Med Res Inst, Singapore, Singapore.
    Shen, Li
    Univ Penn, Dept Biostat Epidemiol & Informat, Philadelphia, PA 19104 USA.
    Saemann, Philipp G.
    Max Planck Inst Psychiat, Munich, Germany.
    Brodaty, Henry
    Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW, Australia;UNSW, Dementia Ctr Res Collaborat, Sydney, NSW, Australia.
    Roffman, Joshua L.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.
    de Geus, Eco J. C.
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands;Vrije Univ, Netherlands Twin Register, Amsterdam, Netherlands;Amsterdam Neurosci, Amsterdam, Netherlands;Vrije Univ Amsterdam Med Ctr, Amsterdam Publ Hlth Res Inst, Amsterdam, Netherlands.
    Tsolaki, Magda
    Aristotle Univ Thessaloniki, Ahepa Univ Hosp, Dept Neurol 1, Thessaloniki, Greece.
    Erk, Susanne
    Freie Univ Berliepartment Psychiat & Psychotherap, Div Mind & Brain Res D, Berlin, Germany;Charite Univ Med Berlin, Berlin, Germany;Humboldt Univ, Berlin, Germany;Berlin Inst Hlth, Berlin, Germany.
    van Eijk, Kristel R.
    UMC Utrecht, Human Neurogenet Unit, Brain Ctr Rudolf Magnus, Utrecht, Netherlands.
    Cavalleri, Gianpiero L.
    Royal Coll Surgeons Ireland, Dept Mol & Cellular Therapeut, Dublin, Ireland.
    van der Wee, Nic J. A.
    Leiden Univ, Dept Psychiat, Med Ctr, Leiden, Netherlands;Leiden Univ, Leiden Inst Brain & Cognit, Med Ctr, Leiden, Netherlands.
    McIntosh, Andrew M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Dept Psychol, Edinburgh, Midlothian, Scotland;Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland.
    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 02115 USA.
    Bulayeva, Kazima B.
    Dagestan State Univ, Dept Evolut & Genet, Makhachkala, Russia.
    Bernard, Manon
    Univ Toronto, Lospital Sick Children, Toronto, ON, Canada.
    Richards, Jennifer S.
    Radboud Univ Nijmegen, Dept Cognit Neurosci, Med Ctr, Nijmegen, Netherlands;Indian Inst Sci, Ctr Brain Res, Bangalore, Karnataka, India;Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands.
    Himali, Jayandra J.
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA.
    Loeffler, Markus
    Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany;Univ Leipzig, LIFE Leipzig Res Ctr Civilizat Dis, Leipzig, Germany.
    Rommelse, Nanda
    Radboud Univ Nijmegen, Dept Psychiat, Med Ctr, Nijmegen, Netherlands;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands;Karakter Child & Adolescent Psychiat Univ Ctr, Nijmegen, Netherlands.
    Hoffmann, Wolfgang
    German Ctr Neurodegenerat Dis, Greifswald, Germany;Univ Med Greifswald, Inst Community Med, Sect Epidemiol Hlth Care & Community Hlth, Greifswald, Germany.
    Westlye, Lars T.
    Oslo Univ Hosp, Div Mental Hlth & Addict, CoE NORMENT, Oslo, Norway;Univ Oslo, Inst Clin Med, CoE NORMENT, Oslo, Norway.
    Hernandez, Maria C. Valdes
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland.
    Hansell, Narelle K.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia;Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.
    van Erp, Theo G. M.
    Univ Calif Irvine, Dept Psychiat & Human Behav, Clin Translat Neurosci Lab, Irvine, CA 92717 USA;Univ Calif Irvine, Ctr Neurobiol Learning & Memory, Irvine, CA 92717 USA.
    Wolf, Christiane
    Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, Wurzburg, Germany.
    Kwok, John B. J.
    Univ Sydney, Brain & Mind Ctr, Sydney, NSW, Australia;Neurosci Res Australia, Sydney, NSW, Australia;Univ New South Wales, Sydney, NSW, Australia.
    Vellas, Bruno
    Univ Toulouse, Dept Internal Med, INSERM U1027, Toulouse, France;Univ Toulouse, Dept Geriatr Med, INSERM U1027, Toulouse, France.
    Heinz, Andreas
    Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, Berlin, Germany.
    Loohuis, Loes M. Olde
    Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA.
    Delanty, Norman
    Royal Coll Surgeons Ireland, Dublin, Ireland;Beaumont Hosp, Neurol Div, Dublin, Ireland.
    Ho, Beng-Choon
    Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 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;UCLA, Sch Med, Interdept Neurosci Grad Program, Los Angeles, CA USA.
    Shumskaya, Elena
    Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Nijmegen, Netherlands;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands;Radboud Univ Nijmegen, Donders Ctr Cognit Neuroimaging, Nijmegen, Netherlands.
    Singh, Baljeet
    Univ Calif Davis, Dept Neurol, Imaging Dementia & Aging Lab, Davis, CA 95616 USA.
    Hofman, Albert
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.
    van der Meer, Dennis
    Oslo Univ Hosp, Div Mental Hlth & Addict, CoE NORMENT, Oslo, Norway;Univ Oslo, Inst Clin Med, CoE NORMENT, Oslo, Norway;Maastricht Univ, Fac Hlth Med & Life Sci, Sch Mental Hlth & Neurosci, Maastricht, Netherlands.
    Homuth, Georg
    Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany.
    Psaty, Bruce M.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA;Kaiser Permanent Washington Hlth Res Inst, Seattle, WA USA;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA;Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA.
    Bastin, Mark E.
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland.
    Montgomery, Grant W.
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia.
    Foroud, Tatiana M.
    Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA;Indiana Univ Sch Med, Med & Mol Genet, Indianapolis, IN 46202 USA.
    Reppermund, Simone
    Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW, Australia;UNSW Med, Dept Dev Disabil Neuropsychiat, Sch Psychiat, Sydney, NSW, Australia.
    Hottenga, Jouke-Jan
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands;Vrije Univ, Netherlands Twin Register, Amsterdam, Netherlands;Amsterdam Neurosci, Amsterdam, Netherlands;Vrije Univ Amsterdam Med Ctr, Amsterdam Publ Hlth Res Inst, Amsterdam, Netherlands.
    Simmons, Andrew
    Kings Coll London, Biomed Res Unit Dementia, London, England;Kings Coll London, Inst Psychiat, Dept Neuroimaging, London, England;Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden.
    Meyer-Lindenberg, Andreas
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Mannheim, Germany.
    Cahn, Wiepke
    Univ Utrecht, Univ Med Ctr Utrecht, UMC Brain Ctr, Dept Psychiat, Utrecht, Netherlands.
    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, Ireland.
    van Donkelaar, Marjolein M. J.
    Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Nijmegen, Netherlands;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.
    Yang, Qiong
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA.
    Hosten, Norbert
    Univ Med Greifswald, Inst Diagnost Radiol & Neuroradiol, Greifswald, Germany.
    Green, Robert C.
    Harvard Med Sch, Boston, MA 02115 USA;Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA.
    Thalamuthu, Anbupalam
    Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW, Australia.
    Mohnke, Sebastian
    Freie Univ Berliepartment Psychiat & Psychotherap, Div Mind & Brain Res D, Berlin, Germany;Charite Univ Med Berlin, Berlin, Germany;Humboldt Univ, Berlin, Germany;Berlin Inst Hlth, Berlin, Germany.
    Pol, Hilleke E. Hulshoff
    Univ Utrecht, Univ Med Ctr Utrecht, UMC Brain Ctr, Dept Psychiat, Utrecht, Netherlands.
    Lin, Honghuang
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;Boston Univ, Sch Med, Dept Med, Sect Computat Biomed, Boston, MA 02118 USA.
    Jack, Clifford R., Jr.
    Mayo Clin, Dept Radiol, Rochester, MN USA.
    Schofield, Peter R.
    Neurosci Res Australia, Sydney, NSW, Australia;UNSW, Sch Med Sci, Sydney, NSW, Australia.
    Muehleisen, Thomas W.
    Res Ctr Julich, Inst Neurosci & Med Struct & Funct Org Brain INM, Julich, Germany;Univ Basel, Dept Biomed, Basel, Switzerland;Heinrich Heine Univ Dusseldorf, Cecile & Oskar Vogt Inst Brain Res, Dusseldorf, Germany.
    Maillard, Pauline
    Univ Calif Davis, Dept Neurol, Imaging Dementia & Aging Lab, Davis, CA 95616 USA.
    Potkin, Steven G.
    Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA.
    Wen, Wei
    Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW, Australia.
    Fletcher, Evan
    Univ Calif Davis, Dept Neurol, Imaging Dementia & Aging Lab, Davis, CA 95616 USA.
    Toga, Arthur W.
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Lab Neuro Imaging, Los Angeles, CA USA.
    Gruber, Oliver
    Heidelberg Univ, Dept Gen Psychiat, Sect Expt Psychopathol & Neuroimaging, Heidelberg, Germany.
    Huentelman, Matthew
    Translat Genom Res Inst, Neurogen Div, Phoenix, AZ USA.
    Smith, George Davey
    Univ Bristol, Bristol Med Sch, MRC Integrat Epidemiol Unit, Bristol, Avon, England.
    Launer, Lenore J.
    NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, NIH, Bethesda, MD 20892 USA.
    Nyberg, Lars
    Umea Univ, Dept Integrat Med Biol, Umea, Sweden;Umea Univ, Umea Ctr Funct Brain Imaging UFBI, Umea, Sweden;Umea Univ, Radiat Sci, Umea, Sweden.
    Jonsson, Erik G.
    Univ Oslo, Inst Clin Med, CoE NORMENT, Oslo, Norway;Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden.
    Crespo-Facorro, Benedicto
    Univ Cantabria IDIVAL, Univ Hosp Marques de Valdecilla, Sch Med, Dept Med, Santander, Spain;Ctr Invest Biomed Red Salud Mental, Santander, Spain.
    Koen, Nastassja
    Univ Cape Town, Dept Psychiat & Mental Hlth, Cape Town, South Africa;South African Med Res Council, Unit Risk & Resilience Mental Disorders, Cape Town, South Africa.
    Greve, Douglas N.
    Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA;Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02115 USA.
    Uitterlinden, Andre G.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands.
    Weinberger, Daniel R.
    Lieber Inst Brain Dev, Baltimore, MD 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, Inst Genet Med, Sch Med, Baltimore, MD USA;Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA.
    Steen, Vidar M.
    Univ Bergen, Dept Clin Sci, NORMENT, Bergen, Norway;Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway.
    Fedko, Iryna O.
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands;Vrije Univ, Netherlands Twin Register, Amsterdam, Netherlands;Vrije Univ Amsterdam Med Ctr, Amsterdam Publ Hlth Res Inst, Amsterdam, Netherlands.
    Groenewold, Nynke A.
    Univ Cape Town, Dept Psychiat & Mental Hlth, Cape Town, South Africa.
    Niessen, Wiro J.
    Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands;Erasmus MC, Dept Med Informat, Rotterdam, Netherlands;Delft Univ Technol, Fac Appl Sci, Imaging Phys, Delft, Netherlands.
    Toro, Roberto
    Inst Pasteur, Paris, France.
    Tzourio, Christophe
    CHU Bordeaux, Dept Neurol, Bordeaux, France.
    Longstreth, William T., Jr.
    Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA;Univ Washington, Dept Neurol, Seattle, WA 98195 USA.
    Ikram, M. Kamran
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Erasmus MC, Dept Neurol, Rotterdam, Netherlands.
    Smoller, Jordan W.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA;Harvard Med Sch, Boston, MA 02115 USA;Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Genom Med, Boston, MA 02114 USA;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Boston, MA USA.
    van Tol, Marie-Jose
    Univ Groningen, Univ Med Ctr Groningen, Cognit Neurosci Ctr, Groningen, Netherlands.
    Sussmann, Jessika E.
    Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland.
    Paus, Tomas
    Holland Bloorview Kids Rehabil Hosp, Bloorview Res Inst, Toronto, ON, Canada;Univ Toronto, Dept Psychol, Toronto, ON, Canada;Univ Toronto, Dept Psychiat, Toronto, ON, Canada.
    Lemaitre, Herve
    Paris Saclay Univ, INSERM, Res Unit Neuroimaging & Psychiat 1000, Gif Sur Yvette, France;Paris Descartes Univ, DIGITEO Labs, Gif Sur Yvette, France.
    Schroeter, Matthias L.
    Univ Leipzig, LIFE Leipzig Res Ctr Civilizat Dis, Leipzig, Germany;Max Planck Inst Human Cognit & Brain Sci, Dept Neurol, Leipzig, Germany;Univ Clin Leipzig, Clin Cognit Neurol, Leipzig, Germany.
    Mazoyer, Bernard
    Univ Bordeaux, Neurodegeneratives Dis Inst, CNRS UMR 5293, Bordeaux, France.
    Andreassen, Ole A.
    Oslo Univ Hosp, Div Mental Hlth & Addict, CoE NORMENT, Oslo, Norway;Univ Oslo, Inst Clin Med, CoE NORMENT, Oslo, Norway.
    Holsboer, Florian
    Max Planck Inst Psychiat, Munich, Germany;HMNC Brain Hlth, Munich, Germany.
    Depondt, Chantal
    Univ Libre Bruxelles, Dept Neurol, Hop Erasme, Brussels, Belgium.
    Veltman, Dick J.
    Vrije Univ Amsterdam, Dept Psychiat, Amsterdam Neurosci, Med Ctr, Amsterdam, Netherlands.
    Turner, Jessica A.
    Mind Res Network, Albuquerque, NM USA;LBERI, Albuquerque, NM USA;Georgia State Univ, Triinst Ctr Translat Res Neuroimaging & Data Sci, Atlanta, GA 30303 USA;Georgia State Univ, Dept Psychol, Univ Plaza, Atlanta, GA 30303 USA.
    Pausova, Zdenka
    Univ Toronto, Lospital Sick Children, Toronto, ON, Canada.
    Schumann, Gunter
    Kings Coll London, MRC SGDP Ctr, Inst Psychiat Psychol & Neurosci, London, England.
    van Rooij, Daan
    Radboud Univ Nijmegen, Dept Cognit Neurosci, Med Ctr, Nijmegen, Netherlands;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands;Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands.
    Djurovic, Srdjan
    Univ Bergen, Dept Clin Sci, NORMENT, Bergen, Norway;Oslo Univ Hosp, Dept Med Genet, Oslo, Norway.
    Deary, Ian J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Dept Psychol, Edinburgh, Midlothian, Scotland.
    McMahon, Katie L.
    Queensland Univ Technol, Fac Hlth, Brisbane, Qld, Australia;Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia.
    Mueller-Myhsok, Bertram
    Max Planck Inst Psychiat, Munich, Germany;Munich Cluster Syst Neurol SyNergy, Munich, Germany;Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England.
    Brouwer, Rachel M.
    Univ Utrecht, Univ Med Ctr Utrecht, UMC Brain Ctr, Dept Psychiat, Utrecht, Netherlands.
    Soininen, Hilkka
    Univ Eastern Finland, Inst Clin Med Neurol, Kuopio, Finland;Kuopio Univ Hosp, Neuroctr Neurol, Kuopio, Finland.
    Pandolfo, Massimo
    Univ Libre Bruxelles, Dept Neurol, Hop Erasme, Brussels, Belgium.
    Wassink, Thomas H.
    Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA.
    Cheung, Joshua W.
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA.
    Wolfers, Thomas
    Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Nijmegen, Netherlands;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.
    Martinot, Jean-Luc
    Paris Saclay Univ, INSERM, Res Unit Neuroimaging & Psychiat 1000, Gif Sur Yvette, France;Paris Descartes Univ, DIGITEO Labs, Gif Sur Yvette, France.
    Zwiers, Marcel P.
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands;Radboud Univ Nijmegen, Donders Ctr Cognit Neuroimaging, Nijmegen, Netherlands.
    Nauck, Matthias
    Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany;German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany.
    Melle, Ingrid
    Oslo Univ Hosp, Div Mental Hlth & Addict, CoE NORMENT, Oslo, Norway;Univ Oslo, Inst Clin Med, CoE NORMENT, Oslo, Norway.
    Martin, Nicholas G.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia.
    Kanai, Ryota
    Araya, Dept Neuroinformat, Tokyo, Japan;UCL, Inst Cognit Neurosci, London, England;Univ Sussex, Sch Psychol, Brighton, E Sussex, England.
    Westman, Eric
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden.
    Kahn, Rene S.
    Univ Utrecht, Univ Med Ctr Utrecht, UMC Brain Ctr, Dept Psychiat, Utrecht, Netherlands;Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA.
    Sisodiya, Sanjay M.
    UCL Queen Sq Inst Neurol, London, England;Chalfont Ctr Epilepsy, Gerrards Cross, Bucks, England.
    White, Tonya
    Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands;Erasmus MC Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands.
    Saremi, Arvin
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA.
    van Bokhoven, Hans
    Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Nijmegen, Netherlands;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.
    Brunner, Han G.
    Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Nijmegen, Netherlands;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands;Maastricht Univ, Dept Clin Genet, Med Ctr, Maastricht, Netherlands;GROW Sch Oncol & Dev Biol, Maastricht, Netherlands.
    Voelzke, Henry
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany;German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany.
    Wright, Margaret J.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia;Univ Queensland, Ctr Adv Imaging, Brisbane, Qld, Australia.
    van't Ent, Dennis
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands;Vrije Univ, Netherlands Twin Register, Amsterdam, Netherlands;Amsterdam Neurosci, Amsterdam, Netherlands;Vrije Univ Amsterdam Med Ctr, Amsterdam Publ Hlth Res Inst, Amsterdam, Netherlands.
    Noethen, Markus M.
    Univ Bonn, Inst Human Genet, Bonn, Germany;Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany.
    Ophoff, Roel A.
    Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA;Erasmus MC, Dept Psychiat, Rotterdam, Netherlands.
    Buitelaar, Jan K.
    Radboud Univ Nijmegen, Dept Cognit Neurosci, Med Ctr, Nijmegen, Netherlands;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands;Karakter Child & Adolescent Psychiat Univ Ctr, Nijmegen, Netherlands.
    Fernandez, Guilln
    Radboud Univ Nijmegen, Dept Cognit Neurosci, Med Ctr, Nijmegen, Netherlands;Indian Inst Sci, Ctr Brain Res, Bangalore, Karnataka, India.
    Sachdev, Perminder S.
    Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW, Australia;Prince Wales Hosp, Neuropsychiat Inst, Sydney, NSW, Australia.
    Rietschel, Marcella
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Mannheim, Germany.
    van Haren, Neeltje E. M.
    Univ Utrecht, Univ Med Ctr Utrecht, UMC Brain Ctr, Dept Psychiat, Utrecht, Netherlands;Erasmus MC Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands.
    Fisher, Simon E.
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands;Max Planck Inst Psycholinguist, Language & Genet Dept, Nijmegen, Netherlands.
    Beiser, Alexa S.
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA.
    Francks, Clyde
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands;Max Planck Inst Psycholinguist, Language & Genet Dept, Nijmegen, Netherlands.
    Saykin, Andrew J.
    Indiana Univ Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN 46202 USA;Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA;Indiana Univ Sch Med, Med & Mol Genet, Indianapolis, IN 46202 USA.
    Mather, Karen A.
    Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW, Australia;Neurosci Res Australia, Sydney, NSW, Australia.
    Romanczuk-Seiferth, Nina
    Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, Berlin, Germany.
    Hartman, Catharina A.
    Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands.
    DeStefano, Anita L.
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA.
    Heslenfeld, Dirk J.
    Vrije Univ Amsterdam, Dept Psychol, Amsterdam, Netherlands.
    Weiner, Michael W.
    Univ Calif San Francisco, Ctr Imaging Neurodegenerat Dis, San Francisco VA Med Ctr, San Francisco, CA 94143 USA;Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA.
    Walter, Henrik
    Freie Univ Berliepartment Psychiat & Psychotherap, Div Mind & Brain Res D, Berlin, Germany;Charite Univ Med Berlin, Berlin, Germany;Humboldt Univ, Berlin, Germany;Berlin Inst Hlth, Berlin, Germany.
    Hoekstra, Pieter J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands.
    Nyquist, Paul A.
    Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Program, Baltimore, MD 21205 USA.
    Franke, Barbara
    Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Nijmegen, Netherlands;Radboud Univ Nijmegen, Dept Psychiat, Med Ctr, Nijmegen, Netherlands;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.
    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.
    Grabe, Hans J.
    Univ Med Greifswald, Dept Psychiat, Greifswald, Germany;German Ctr Neurodegenerat Dis, Greifswald, Germany.
    Johnson, Andrew D.
    NHLBI, Div Intramural Res, Populat Sci Branch, Framingham, MA USA.
    Chen, Christopher
    Natl Univ Singapore, Dept Pharmacol, Singapore, Singapore;Natl Univ Hlth Syst, Memory Aging & Cognit Ctr, Singapore, Singapore.
    van Duijn, Cornelia M.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Leiden Univ, Leiden Acad Ctr Drug Res, Leiden, Netherlands.
    Lopez, Oscar L.
    Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA;Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA.
    Fornage, Myriam
    Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Houston, TX 77030 USA;Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX 77030 USA.
    Wardlaw, Joanna M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Dept Psychol, Edinburgh, Midlothian, Scotland;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland;Univ Edinburgh, UK Dementia Res Inst, Edinburgh, Midlothian, Scotland.
    Schmidt, Reinhold
    Med Univ Graz, Dept Neurol, Clin Div Neurogeriatr, Graz, Austria.
    DeCarli, Charles
    Univ Calif Davis, Ctr Neurosci, Dept Neurol, Sacramento, CA 95817 USA.
    De Jager, Philip L.
    Broad Inst, Cell Circuits Program, Cambridge, MA USA;Columbia Univ, Dept Neurol, Med Ctr, Ctr Translat & Computat Neuroimmunol, New York, NY USA.
    Villringer, Arno
    Max Planck Inst Human Cognit & Brain Sci, Dept Neurol, Leipzig, Germany;Univ Leipzig, Fac Med, CRC Obes Mech 1052, Leipzig, Germany.
    Debette, Stephanie
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA;Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, Team Vintage, INSERM,UMR 1219, Bordeaux, France;CHU Bordeaux, Dept Neurol, Bordeaux, France.
    Gudnason, Vilmundur
    Univ Iceland, Fac Med, Reykjavik, Iceland;Iceland Heart Assoc, Kopavogur, Iceland.
    Medland, Sarah E.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia.
    Shulman, Joshua M.
    Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA;Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA;Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA;Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA.
    Thompson, Paul M.
    Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA.
    Seshadri, Sudha
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.
    Ikram, M. Arfan
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands.
    Genetic architecture of subcortical brain structures in 38,851 individuals2019In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 11, p. 1624-+Article in journal (Refereed)
    Abstract [en]

    Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

  • 266. Sawcer, Stephen
    et al.
    Hellenthal, Garrett
    Pirinen, Matti
    Spencer, Chris C. A.
    Patsopoulos, Nikolaos A.
    Moutsianas, Loukas
    Dilthey, Alexander
    Su, Zhan
    Freeman, Colin
    Hunt, Sarah E.
    Edkins, Sarah
    Gray, Emma
    Booth, David R.
    Potter, Simon C.
    Goris, An
    Band, Gavin
    Oturai, Annette Bang
    Strange, Amy
    Saarela, Janna
    Bellenguez, Celine
    Fontaine, Bertrand
    Gillman, Matthew
    Hemmer, Bernhard
    Gwilliam, Rhian
    Zipp, Frauke
    Jayakumar, Alagurevathi
    Martin, Roland
    Leslie, Stephen
    Hawkins, Stanley
    Giannoulatou, Eleni
    D'alfonso, Sandra
    Blackburn, Hannah
    Boneschi, Filippo Martinelli
    Liddle, Jennifer
    Harbo, Hanne F.
    Perez, Marc L.
    Spurkland, Anne
    Waller, Matthew J.
    Mycko, Marcin P.
    Ricketts, Michelle
    Comabella, Manuel
    Hammond, Naomi
    Kockum, Ingrid
    McCann, Owen T.
    Ban, Maria
    Whittaker, Pamela
    Kemppinen, Anu
    Weston, Paul
    Hawkins, Clive
    Widaa, Sara
    Zajicek, John
    Dronov, Serge
    Robertson, Neil
    Bumpstead, Suzannah J.
    Barcellos, Lisa F.
    Ravindrarajah, Rathi
    Abraham, Roby
    Alfredsson, Lars
    Ardlie, Kristin
    Aubin, Cristin
    Baker, Amie
    Baker, Katharine
    Baranzini, Sergio E.
    Bergamaschi, Laura
    Bergamaschi, Roberto
    Bernstein, Allan
    Berthele, Achim
    Boggild, Mike
    Bradfield, Jonathan P.
    Brassat, David
    Broadley, Simon A.
    Buck, Dorothea
    Butzkueven, Helmut
    Capra, Ruggero
    Carroll, William M.
    Cavalla, Paola
    Celius, Elisabeth G.
    Cepok, Sabine
    Chiavacci, Rosetta
    Clerget-Darpoux, Francoise
    Clysters, Katleen
    Comi, Giancarlo
    Cossburn, Mark
    Cournu-Rebeix, Isabelle
    Cox, Mathew B.
    Cozen, Wendy
    Cree, Bruce A. C.
    Cross, Anne H.
    Cusi, Daniele
    Daly, Mark J.
    Davis, Emma
    de Bakker, Paul I. W.
    Debouverie, Marc
    D'hooghe, Marie Beatrice
    Dixon, Katherine
    Dobosi, Rita
    Dubois, Benedicte
    Ellinghaus, David
    Elovaara, Irina
    Esposito, Federica
    Fontenille, Claire
    Foote, Simon
    Franke, Andre
    Galimberti, Daniela
    Ghezzi, Angelo
    Glessner, Joseph
    Gomez, Refujia
    Gout, Olivier
    Graham, Colin
    Grant, Struan F. A.
    Guerini, Franca Rosa
    Hakonarson, Hakon
    Hall, Per
    Hamsten, Anders
    Hartung, Hans-Peter
    Heard, Rob N.
    Heath, Simon
    Hobart, Jeremy
    Hoshi, Muna
    Infante-Duarte, Carmen
    Ingram, Gillian
    Ingram, Wendy
    Islam, Talat
    Jagodic, Maja
    Kabesch, Michael
    Kermode, Allan G.
    Kilpatrick, Trevor J.
    Kim, Cecilia
    Klopp, Norman
    Koivisto, Keijo
    Larsson, Malin
    Lathrop, Mark
    Lechner-Scott, Jeannette S.
    Leone, Maurizio A.
    Leppa, Virpi
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bomfim, Izaura Lima
    Lincoln, Robin R.
    Link, Jenny
    Liu, Jianjun
    Lorentzen, Aslaug R.
    Lupoli, Sara
    Macciardi, Fabio
    Mack, Thomas
    Marriott, Mark
    Martinelli, Vittorio
    Mason, Deborah
    McCauley, Jacob L.
    Mentch, Frank
    Mero, Inger-Lise
    Mihalova, Tania
    Montalban, Xavier
    Mottershead, John
    Myhr, Kjell-Morten
    Naldi, Paola
    Ollier, William
    Page, Alison
    Palotie, Aarno
    Pelletier, Jean
    Piccio, Laura
    Pickersgill, Trevor
    Piehl, Fredrik
    Pobywajlo, Susan
    Quach, Hong L.
    Ramsay, Patricia P.
    Reunanen, Mauri
    Reynolds, Richard
    Rioux, Johnd.
    Rodegher, Mariaemma
    Roesner, Sabine
    Rubio, Justin P.
    Rueckert, Ina-Maria
    Salvetti, Marco
    Salvi, Erika
    Santaniello, Adam
    Schaefer, Catherine A.
    Schreiber, Stefan
    Schulze, Christian
    Scott, Rodney J.
    Sellebjerg, Finn
    Selmaj, Krzysztof W.
    Sexton, David
    Shen, Ling
    Simms-Acuna, Brigid
    Skidmore, Sheila
    Sleiman, Patrick M. A.
    Smestad, Cathrine
    Sorensen, Per Soelberg
    Sondergaard, Helle Bach
    Stankovich, Jim
    Strange, Richard C.
    Sulonen, Anna-Maija
    Sundqvist, Emilie
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Taddeo, Francesca
    Taylor, Bruce
    Blackwell, Jenefer M.
    Tienari, Pentti
    Bramon, Elvira
    Tourbah, Ayman
    Brown, Matthew A.
    Tronczynska, Ewa
    Casas, Juan P.
    Tubridy, Niall
    Corvin, Aiden
    Vickery, Jane
    Jankowski, Janusz
    Villoslada, Pablo
    Markus, Hugh S.
    Wang, Kai
    Mathew, Christopher G.
    Wason, James
    Palmer, Colin N. A.
    Wichmann, H-Erich
    Plomin, Robert
    Willoughby, Ernest
    Rautanen, Anna
    Winkelmann, Juliane
    Wittig, Michael
    Trembath, Richard C.
    Yaouanq, Jacqueline
    Viswanathan, Ananth C.
    Zhang, Haitao
    Wood, Nicholas W.
    Zuvich, Rebecca
    Deloukas, Panos
    Langford, Cordelia
    Duncanson, Audrey
    Oksenberg, Jorge R.
    Pericak-Vance, Margaret A.
    Haines, Jonathan L.
    Olsson, Tomas
    Hillert, Jan
    Ivinson, Adrian J.
    De Jager, Philip L.
    Peltonen, Leena
    Stewart, Graeme J.
    Hafler, David A.
    Hauser, Stephen L.
    McVean, Gil
    Donnelly, Peter
    Compston, Alastair
    Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis2011In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 476, no 7359, p. 214-219Article in journal (Refereed)
    Abstract [en]

    Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

  • 267. Saxena, Richa
    et al.
    Hivert, Marie-France
    Langenberg, Claudia
    Tanaka, Toshiko
    Pankow, James S
    Vollenweider, Peter
    Lyssenko, Valeriya
    Bouatia-Naji, Nabila
    Dupuis, Josée
    Jackson, Anne U
    Kao, W H Linda
    Li, Man
    Glazer, Nicole L
    Manning, Alisa K
    Luan, Jian'an
    Stringham, Heather M
    Prokopenko, Inga
    Johnson, Toby
    Grarup, Niels
    Boesgaard, Trine W
    Lecoeur, Cécile
    Shrader, Peter
    O'Connell, Jeffrey
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Couper, David J
    Rice, Kenneth
    Song, Kijoung
    Andreasen, Camilla H
    Dina, Christian
    Köttgen, Anna
    Le Bacquer, Olivier
    Pattou, François
    Taneera, Jalal
    Steinthorsdottir, Valgerdur
    Rybin, Denis
    Ardlie, Kristin
    Sampson, Michael
    Qi, Lu
    van Hoek, Mandy
    Weedon, Michael N
    Aulchenko, Yurii S
    Voight, Benjamin F
    Grallert, Harald
    Balkau, Beverley
    Bergman, Richard N
    Bielinski, Suzette J
    Bonnefond, Amelie
    Bonnycastle, Lori L
    Borch-Johnsen, Knut
    Böttcher, Yvonne
    Brunner, Eric
    Buchanan, Thomas A
    Bumpstead, Suzannah J
    Cavalcanti-Proença, Christine
    Charpentier, Guillaume
    Chen, Yii-Der Ida
    Chines, Peter S
    Collins, Francis S
    Cornelis, Marilyn
    J Crawford, Gabriel
    Delplanque, Jerome
    Doney, Alex
    Egan, Josephine M
    Erdos, Michael R
    Firmann, Mathieu
    Forouhi, Nita G
    Fox, Caroline S
    Goodarzi, Mark O
    Graessler, Jürgen
    Hingorani, Aroon
    Isomaa, Bo
    Jørgensen, Torben
    Kivimaki, Mika
    Kovacs, Peter
    Krohn, Knut
    Kumari, Meena
    Lauritzen, Torsten
    Lévy-Marchal, Claire
    Mayor, Vladimir
    McAteer, Jarred B
    Meyre, David
    Mitchell, Braxton D
    Mohlke, Karen L
    Morken, Mario A
    Narisu, Narisu
    Palmer, Colin N A
    Pakyz, Ruth
    Pascoe, Laura
    Payne, Felicity
    Pearson, Daniel
    Rathmann, Wolfgang
    Sandbaek, Annelli
    Sayer, Avan Aihie
    Scott, Laura J
    Sharp, Stephen J
    Sijbrands, Eric
    Singleton, Andrew
    Siscovick, David S
    Smith, Nicholas L
    Sparsø, Thomas
    Swift, Amy J
    Syddall, Holly
    Thorleifsson, Gudmar
    Tönjes, Anke
    Tuomi, Tiinamaija
    Tuomilehto, Jaakko
    Valle, Timo T
    Waeber, Gérard
    Walley, Andrew
    Waterworth, Dawn M
    Zeggini, Eleftheria
    Zhao, Jing Hua
    Illig, Thomas
    Wichmann, H Erich
    Wilson, James F
    van Duijn, Cornelia
    Hu, Frank B
    Morris, Andrew D
    Frayling, Timothy M
    Hattersley, Andrew T
    Thorsteinsdottir, Unnur
    Stefansson, Kari
    Nilsson, Peter
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Shuldiner, Alan R
    Walker, Mark
    Bornstein, Stefan R
    Schwarz, Peter
    Williams, Gordon H
    Nathan, David M
    Kuusisto, Johanna
    Laakso, Markku
    Cooper, Cyrus
    Marmot, Michael
    Ferrucci, Luigi
    Mooser, Vincent
    Stumvoll, Michael
    Loos, Ruth J F
    Altshuler, David
    Psaty, Bruce M
    Rotter, Jerome I
    Boerwinkle, Eric
    Hansen, Torben
    Pedersen, Oluf
    Florez, Jose C
    McCarthy, Mark I
    Boehnke, Michael
    Barroso, Inês
    Sladek, Robert
    Froguel, Philippe
    Meigs, James B
    Groop, Leif
    Wareham, Nicholas J
    Watanabe, Richard M
    Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge2010In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 42, no 2, p. 142-148Article in journal (Refereed)
    Abstract [en]

    Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958–30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, β (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 × 10−15). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 × 10−17; ratio of insulin to glucose area under the curve, P = 1.3 × 10−16) and diminished incretin effect (n = 804; P = 4.3 × 10−4). We also identified variants at ADCY5 (rs2877716, P = 4.2 × 10−16), VPS13C (rs17271305, P = 4.1 × 10−8), GCKR (rs1260326, P = 7.1 × 10−11) and TCF7L2 (rs7903146, P = 4.2 × 10−10) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09–1.15, P = 4.8 × 10−18).

  • 268.
    Sayyab, Shumaila
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundmark, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Malin
    Linköping Univ, Dept Phys Chem & Biol, Sci Life Lab, Natl Bioinformat Infrastruct Sweden, Linköping, Sweden..
    Ringner, Markus
    Lund Univ, Dept Biol, Sci Life Lab, Natl Bioinformat Infrastruct Sweden, Lund, Sweden..
    Nystedt, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Marincevic-Zuniga, Yanara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tamm, Katja Pokrovskaja
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Abrahamsson, Jonas
    Univ Gothenburg, Inst Clin Sci, Dept Pediat, Sahlgrenska Acad, Gothenburg, Sweden.;Nordic Soc Pediat Hematol & Oncol, Stockholm, Sweden..
    Fogelstrand, Linda
    Univ Gothenburg, Inst Biomed, Dept Lab Med, Sahlgrenska Acad, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Clin Chem, Gothenburg, Sweden.;Nordic Soc Pediat Hematol & Oncol, Stockholm, Sweden..
    Heyman, Mats
    Karolinska Univ Hosp, Childhood Canc Res Unit, Stockholm, Sweden.;Nordic Soc Pediat Hematol & Oncol, Stockholm, Sweden..
    Noren-Nystrom, Ulrika
    Univ Umeå, Dept Clin Sci & Pediat, Umeå, Sweden.;Nordic Soc Pediat Hematol & Oncol, Stockholm, Sweden..
    Lönnerholm, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Harila-Saari, Arja H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology. Uppsala Univ, Dept Womens & Childrens Hlth, Uppsala, Sweden.;Nordic Soc Pediat Hematol & Oncol, Stockholm, Sweden..
    Berglund, Eva Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 15988Article in journal (Refereed)
    Abstract [en]

    The mechanisms driving clonal heterogeneity and evolution in relapsed pediatric acute lymphoblastic leukemia (ALL) are not fully understood. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients. Somatic point mutations and large-scale structural variants were called using individually matched remission samples as controls, and allelic expression of the mutations was assessed in ALL cells using RNA-sequencing. We observed an increased burden of somatic mutations at relapse, compared to diagnosis, and at second relapse compared to first relapse. In addition to 29 known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, we identified putative non-protein coding mutations in regulatory regions of seven additional genes that have not previously been described in ALL. Cluster analysis of hundreds of somatic mutations per sample revealed three distinct evolutionary trajectories during ALL progression from diagnosis to relapse. The evolutionary trajectories provide insight into the mutational mechanisms leading relapse in ALL and could offer biomarkers for improved risk prediction in individual patients.

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  • 269. Schnorrer, Frank
    et al.
    Ahlford, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Chen, Doris
    Milani, Lili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Positional cloning by fast-track SNP-mapping in Drosophila melanogaster2008In: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 3, no 11, p. 1751-1765Article in journal (Refereed)
    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.

  • 270.
    Segelbacher, Gernot
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Strand, Tanja M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Quintela, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Jansman, Hugh A.H.
    Koelewijn, Hans-Peter
    Höglund, Jacob
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Analyses of historical and current populations of black grouse in Central Europe reveal strong effects of genetic drift and loss of genetic diversity2014In: Conservation Genetics, ISSN 1566-0621, E-ISSN 1572-9737, Vol. 15, no 5, p. 1183-1195Article in journal (Refereed)
    Abstract [en]

    Black grouse (Tetrao tetrix) in Central Europe have undergone a severe contraction of their range in recent decades with only a few small isolated remaining populations. Here we compare genetic diversity of two contemporary isolated populations (Sallandse Heuvelrug, Netherlands and Lüneburger Heide, Germany) with historical samples from the same region collected within the last one hundred years. We use markers with both putatively neutral and functional variation to test whether the present small and highly fragmented populations hold lower genetic diversity compared to the former larger population. For this we applied three different types of genetic markers: nine microsatellites and 21 single nucleotide polymorphisms (SNPs), both sets which have been found to be neutral, and two functional major histocompatibility complex (MHC) genes for which there is evidence they are under selection. The contemporary small isolated populations displayed lower neutral genetic diversity compared to the corresponding historical samples. Furthermore, samples from Denmark showed that this now extinct population displayed lower genetic variation in the period immediately prior to the local extinction. Population structure was more pronounced among contemporary populations compared to historical populations for microsatellites and SNPs. This effect was not as distinct for MHC which is consistent with the possibility that MHC has been subjected to balancing selection in the past, a process which maintains genetic variation and may minimize population structure for such markers. Genetic differentiation among the present populations highlights the strong effects of population decline on the genetic structure of natural populations, which can be ultimately attributed to habitat loss following anthropogenic land use changes.

  • 271. Sehat, Bita
    et al.
    Tofigh, Ali
    Lin, Yingbo
    Trocmé, Eric
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Lagergren, Jens
    Larsson, Olle
    SUMOylation mediates the nuclear translocation and signaling of the IGF-1 receptor2010In: Science Signaling, ISSN 1937-9145, Vol. 3, no 108, p. ra10-Article in journal (Refereed)
    Abstract [en]

    The insulin-like growth factor 1 receptor (IGF-1R) plays crucial roles in developmental and cancer biology. Most of its biological effects have been ascribed to its tyrosine kinase activity, which propagates signaling through the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. Here, we report that IGF-1 promotes the modification of IGF-1R by small ubiquitin-like modifier protein-1 (SUMO-1) and its translocation to the nucleus. Nuclear IGF-1R associated with enhancer-like elements and increased transcription in reporter assays. The SUMOylation sites of IGF-1R were identified as three evolutionarily conserved lysine residues-Lys(1025), Lys(1100), and Lys(1120)-in the beta subunit of the receptor. Mutation of these SUMO-1 sites abolished the ability of IGF-1R to translocate to the nucleus and activate transcription but did not alter its kinase-dependent signaling. Thus, we demonstrate a SUMOylation-mediated mechanism of IGF-1R signaling that has potential implications for gene regulation.

  • 272. Shungin, Dmitry
    et al.
    Winkler, Thomas W
    Croteau-Chonka, Damien C
    Ferreira, Teresa
    Locke, Adam E
    Mägi, Reedik
    Strawbridge, Rona J
    Pers, Tune H
    Fischer, Krista
    Justice, Anne E
    Workalemahu, Tsegaselassie
    Wu, Joseph M W
    Buchkovich, Martin L
    Heard-Costa, Nancy L
    Roman, Tamara S
    Drong, Alexander W
    Song, Ci
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Day, Felix R
    Esko, Tonu
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kutalik, Zoltán
    Luan, Jian'an
    Randall, Joshua C
    Scherag, André
    Vedantam, Sailaja
    Wood, Andrew R
    Chen, Jin
    Fehrmann, Rudolf
    Karjalainen, Juha
    Kahali, Bratati
    Liu, Ching-Ti
    Schmidt, Ellen M
    Absher, Devin
    Amin, Najaf
    Anderson, Denise
    Beekman, Marian
    Bragg-Gresham, Jennifer L
    Buyske, Steven
    Demirkan, Ayse
    Ehret, Georg B
    Feitosa, Mary F
    Goel, Anuj
    Jackson, Anne U
    Johnson, Toby
    Kleber, Marcus E
    Kristiansson, Kati
    Mangino, Massimo
    Mateo Leach, Irene
    Medina-Gomez, Carolina
    Palmer, Cameron D
    Pasko, Dorota
    Pechlivanis, Sonali
    Peters, Marjolein J
    Prokopenko, Inga
    Stančáková, Alena
    Ju Sung, Yun
    Tanaka, Toshiko
    Teumer, Alexander
    Van Vliet-Ostaptchouk, Jana V
    Yengo, Loïc
    Zhang, Weihua
    Albrecht, Eva
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Arscott, Gillian M
    Bandinelli, Stefania
    Barrett, Amy
    Bellis, Claire
    Bennett, Amanda J
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Blüher, Matthias
    Böhringer, Stefan
    Bonnet, Fabrice
    Böttcher, Yvonne
    Bruinenberg, Marcel
    Carba, Delia B
    Caspersen, Ida H
    Clarke, Robert
    Daw, E Warwick
    Deelen, Joris
    Deelman, Ewa
    Delgado, Graciela
    Doney, Alex S F
    Eklund, Niina
    Erdos, Michael R
    Estrada, Karol
    Eury, Elodie
    Friedrich, Nele
    Garcia, Melissa E
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gigante, Bruna
    Go, Alan S
    Golay, Alain
    Grallert, Harald
    Grammer, Tanja B
    Gräßler, Jürgen
    Grewal, Jagvir
    Groves, Christopher J
    Haller, Toomas
    Hallmans, Goran
    Hartman, Catharina A
    Hassinen, Maija
    Hayward, Caroline
    Heikkilä, Kauko
    Herzig, Karl-Heinz
    Helmer, Quinta
    Hillege, Hans L
    Holmen, Oddgeir
    Hunt, Steven C
    Isaacs, Aaron
    Ittermann, Till
    James, Alan L
    Johansson, Ingegerd
    Juliusdottir, Thorhildur
    Kalafati, Ioanna-Panagiota
    Kinnunen, Leena
    Koenig, Wolfgang
    Kooner, Ishminder K
    Kratzer, Wolfgang
    Lamina, Claudia
    Leander, Karin
    Lee, Nanette R
    Lichtner, Peter
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lindström, Jaana
    Lobbens, Stéphane
    Lorentzon, Mattias
    Mach, François
    Magnusson, Patrik K E
    Mahajan, Anubha
    McArdle, Wendy L
    Menni, Cristina
    Merger, Sigrun
    Mihailov, Evelin
    Milani, Lili
    Mills, Rebecca
    Moayyeri, Alireza
    Monda, Keri L
    Mooijaart, Simon P
    Mühleisen, Thomas W
    Mulas, Antonella
    Müller, Gabriele
    Müller-Nurasyid, Martina
    Nagaraja, Ramaiah
    Nalls, Michael A
    Narisu, Narisu
    Glorioso, Nicola
    Nolte, Ilja M
    Olden, Matthias
    Rayner, Nigel W
    Renstrom, Frida
    Ried, Janina S
    Robertson, Neil R
    Rose, Lynda M
    Sanna, Serena
    Scharnagl, Hubert
    Scholtens, Salome
    Sennblad, Bengt
    Seufferlein, Thomas
    Sitlani, Colleen M
    Vernon Smith, Albert
    Stirrups, Kathleen
    Stringham, Heather M
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Swertz, Morris A
    Swift, Amy J
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tayo, Bamidele O
    Thorand, Barbara
    Thorleifsson, Gudmar
    Tomaschitz, Andreas
    Troffa, Chiara
    van Oort, Floor V A
    Verweij, Niek
    Vonk, Judith M
    Waite, Lindsay L
    Wennauer, Roman
    Wilsgaard, Tom
    Wojczynski, Mary K
    Wong, Andrew
    Zhang, Qunyuan
    Hua Zhao, Jing
    Brennan, Eoin P
    Choi, Murim
    Eriksson, Per
    Folkersen, Lasse
    Franco-Cereceda, Anders
    Gharavi, Ali G
    Hedman, Åsa K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hivert, Marie-France
    Huang, Jinyan
    Kanoni, Stavroula
    Karpe, Fredrik
    Keildson, Sarah
    Kiryluk, Krzysztof
    Liang, Liming
    Lifton, Richard P
    Ma, Baoshan
    McKnight, Amy J
    McPherson, Ruth
    Metspalu, Andres
    Min, Josine L
    Moffatt, Miriam F
    Montgomery, Grant W
    Murabito, Joanne M
    Nicholson, George
    Nyholt, Dale R
    Olsson, Christian
    Perry, John R B
    Reinmaa, Eva
    Salem, Rany M
    Sandholm, Niina
    Schadt, Eric E
    Scott, Robert A
    Stolk, Lisette
    Vallejo, Edgar E
    Westra, Harm-Jan
    Zondervan, Krina T
    Amouyel, Philippe
    Arveiler, Dominique
    Bakker, Stephan J L
    Beilby, John
    Bergman, Richard N
    Blangero, John
    Brown, Morris J
    Burnier, Michel
    Campbell, Harry
    Chakravarti, Aravinda
    Chines, Peter S
    Claudi-Boehm, Simone
    Collins, Francis S
    Crawford, Dana C
    Danesh, John
    de Faire, Ulf
    de Geus, Eco J C
    Dörr, Marcus
    Erbel, Raimund
    Eriksson, Johan G
    Farrall, Martin
    Ferrannini, Ele
    Ferrières, Jean
    Forouhi, Nita G
    Forrester, Terrence
    Franco, Oscar H
    Gansevoort, Ron T
    Gieger, Christian
    Gudnason, Vilmundur
    Haiman, Christopher A
    Harris, Tamara B
    Hattersley, Andrew T
    Heliövaara, Markku
    Hicks, Andrew A
    Hingorani, Aroon D
    Hoffmann, Wolfgang
    Hofman, Albert
    Homuth, Georg
    Humphries, Steve E
    Hyppönen, Elina
    Illig, Thomas
    Jarvelin, Marjo-Riitta
    Johansen, Berit
    Jousilahti, Pekka
    Jula, Antti M
    Kaprio, Jaakko
    Kee, Frank
    Keinanen-Kiukaanniemi, Sirkka M
    Kooner, Jaspal S
    Kooperberg, Charles
    Kovacs, Peter
    Kraja, Aldi T
    Kumari, Meena
    Kuulasmaa, Kari
    Kuusisto, Johanna
    Lakka, Timo A
    Langenberg, Claudia
    Le Marchand, Loic
    Lehtimäki, Terho
    Lyssenko, Valeriya
    Männistö, Satu
    Marette, André
    Matise, Tara C
    McKenzie, Colin A
    McKnight, Barbara
    Musk, Arthur W
    Möhlenkamp, Stefan
    Morris, Andrew D
    Nelis, Mari
    Ohlsson, Claes
    Oldehinkel, Albertine J
    Ong, Ken K
    Palmer, Lyle J
    Penninx, Brenda W
    Peters, Annette
    Pramstaller, Peter P
    Raitakari, Olli T
    Rankinen, Tuomo
    Rao, D C
    Rice, Treva K
    Ridker, Paul M
    Ritchie, Marylyn D
    Rudan, Igor
    Salomaa, Veikko
    Samani, Nilesh J
    Saramies, Jouko
    Sarzynski, Mark A
    Schwarz, Peter E H
    Shuldiner, Alan R
    Staessen, Jan A
    Steinthorsdottir, Valgerdur
    Stolk, Ronald P
    Strauch, Konstantin
    Tönjes, Anke
    Tremblay, Angelo
    Tremoli, Elena
    Vohl, Marie-Claude
    Völker, Uwe
    Vollenweider, Peter
    Wilson, James F
    Witteman, Jacqueline C
    Adair, Linda S
    Bochud, Murielle
    Boehm, Bernhard O
    Bornstein, Stefan R
    Bouchard, Claude
    Cauchi, Stéphane
    Caulfield, Mark J
    Chambers, John C
    Chasman, Daniel I
    Cooper, Richard S
    Dedoussis, George
    Ferrucci, Luigi
    Froguel, Philippe
    Grabe, Hans-Jörgen
    Hamsten, Anders
    Hui, Jennie
    Hveem, Kristian
    Jöckel, Karl-Heinz
    Kivimaki, Mika
    Kuh, Diana
    Laakso, Markku
    Liu, Yongmei
    März, Winfried
    Munroe, Patricia B
    Njølstad, Inger
    Oostra, Ben A
    Palmer, Colin N A
    Pedersen, Nancy L
    Perola, Markus
    Pérusse, Louis
    Peters, Ulrike
    Power, Chris
    Quertermous, Thomas
    Rauramaa, Rainer
    Rivadeneira, Fernando
    Saaristo, Timo E
    Saleheen, Danish
    Sinisalo, Juha
    Slagboom, P Eline
    Snieder, Harold
    Spector, Tim D
    Thorsteinsdottir, Unnur
    Stumvoll, Michael
    Tuomilehto, Jaakko
    Uitterlinden, André G
    Uusitupa, Matti
    van der Harst, Pim
    Veronesi, Giovanni
    Walker, Mark
    Wareham, Nicholas J
    Watkins, Hugh
    Wichmann, H-Erich
    Abecasis, Goncalo R
    Assimes, Themistocles L
    Berndt, Sonja I
    Boehnke, Michael
    Borecki, Ingrid B
    Deloukas, Panos
    Franke, Lude
    Frayling, Timothy M
    Groop, Leif C
    Hunter, David J
    Kaplan, Robert C
    O'Connell, Jeffrey R
    Qi, Lu
    Schlessinger, David
    Strachan, David P
    Stefansson, Kari
    van Duijn, Cornelia M
    Willer, Cristen J
    Visscher, Peter M
    Yang, Jian
    Hirschhorn, Joel N
    Zillikens, M Carola
    McCarthy, Mark I
    Speliotes, Elizabeth K
    North, Kari E
    Fox, Caroline S
    Barroso, Inês
    Franks, Paul W
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Heid, Iris M
    Loos, Ruth J F
    Cupples, L Adrienne
    Morris, Andrew P
    Lindgren, Cecilia M
    Mohlke, Karen L
    New genetic loci link adipose and insulin biology to body fat distribution2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 518, no 7538, p. 187-196Article in journal (Refereed)
    Abstract [en]

    Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

  • 273.
    Sigurdsson, Snaevar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Göring, Harald H. H.
    Kristjansdottir, Gudlaug
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Milani, Lili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Feng, Di
    Sangster-Guity, Niquiche
    Gunnarsson, Iva
    Svenungsson, Elisabet
    Sturfelt, Gunnar
    Jönsen, Andreas
    Truedsson, Lennart
    Barnes, Betsy J.
    Alm, Gunnar
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Comprehensive evaluation of the genetic variants of interferon regulatory factor 5 (IRF5) reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus2008In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 17, no 6, p. 872-881Article in journal (Refereed)
    Abstract [en]

    We analyzed a comprehensive set of single-nucleotide polymorphisms (SNPs) and length polymorphisms in the interferon regulatory factor 5 (IRF5) gene for their association with the autoimmune disease systemic lupus erythematosus (SLE) in 485 Swedish patients and 563 controls. We found 16 SNPs and two length polymorphisms that display association with SLE (P < 0.0005, OR > 1.4). Using a Bayesian model selection and averaging approach we identified parsimonious models with exactly two variants of IRF5 that are independently associated with SLE. The variants of IRF5 with the highest posterior probabilities (1.00 and 0.71, respectively) of being causal in SLE are a SNP (rs10488631) located 3' of IRF5, and a novel CGGGG insertion-deletion (indel) polymorphism located 64 bp upstream of the first untranslated exon (exon 1A) of IRF5. The CGGGG indel explains the association signal from multiple SNPs in the IRF5 gene, including rs2004640, rs10954213 and rs729302 previously considered to be causal variants in SLE. The CGGGG indel contains three or four repeats of the sequence CGGGG with the longer allele containing an additional SP1 binding site as the risk allele for SLE. Using electrophoretic mobility shift assays we show increased binding of protein to the risk allele of the CGGGG indel and using a minigene reporter assay we show increased expression of IRF5 mRNA from a promoter containing this allele. Increased expression of IRF5 protein was observed in peripheral blood mononuclear cells from SLE patients carrying the risk allele of the CGGGG indel. We have found that the same IRF5 allele also confers risk for inflammatory bowel diseases and multiple sclerosis, suggesting a general role for IRF5 in autoimmune diseases.

  • 274.
    Sigurdsson, Snaevar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Hedman, Minttu
    Sistonen, Pertti
    Sajantila, Antti
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    A microarray system for genotyping 150 single nucleotide polymorphisms in the coding region of human mitochondrial DNA2006In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 87, no 4, p. 534-542Article in journal (Refereed)
    Abstract [en]

    We established a genotyping system for a panel of 150 SNPs in the coding regions of mitochondrial DNA based on multiplex tag-array minisequencing. We show the feasibility of this system for simultaneous identification of individuals and prediction of the geographical origin of the mitochondrial DNA population lineage of the sample donors by genotyping the panel of SNPs in 265 samples representing nine different populations from Africa, Europe, and Asia. Nearly 40,000 genotypes were produced in the study, with an overall genotyping success rate of 95% and accuracy close to 100%. The gene diversity value of the panel of 150 SNPs was 0.991, compared to 0.995 for sequencing 500 nucleotides of the hypervariable regions I and II of mtDNA. For 17 individuals with identical sequences in the hypervariable regions of mtDNA, our panel of SNPs increased the power of discrimination. We observed 144 haplotypes that correspond to previously determined mitochondrial “haplogroups,” and they allowed prediction of the origin of the maternal population lineage of 97% of the analyzed samples.

  • 275.
    Sigurdsson, Snaevar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Garnier, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Grundberg, Elin
    Kwan, Tony
    Nilsson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gunnarsson, Iva
    Svenungsson, Elisabet
    Sturfelt, Gunnar
    Bengtsson, Anders A.
    Jönsen, Andreas
    Truedsson, Lennart
    Rantapää-Dahlqvist, Solbritt
    Eriksson, Catharina
    Alm, Gunnar
    Göring, Harald H. H.
    Pastinen, Tomi
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF52008In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 17, no 18, p. 2868-2876Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is the prototype autoimmune disease where genes regulated by type I interferon (IFN) are over-expressed and contribute to the disease pathogenesis. Because signal transducer and activator of transcription 4 (STAT4) plays a key role in the type I IFN receptor signaling, we performed a candidate gene study of a comprehensive set of single nucleotide polymorphism (SNPs) in STAT4 in Swedish patients with SLE. We found that 10 out of 53 analyzed SNPs in STAT4 were associated with SLE, with the strongest signal of association (P = 7.1 x 10(-8)) for two perfectly linked SNPs rs10181656 and rs7582694. The risk alleles of these 10 SNPs form a common risk haplotype for SLE (P = 1.7 x 10(-5)). According to conditional logistic regression analysis the SNP rs10181656 or rs7582694 accounts for all of the observed association signal. By quantitative analysis of the allelic expression of STAT4 we found that the risk allele of STAT4 was over-expressed in primary human cells of mesenchymal origin, but not in B-cells, and that the risk allele of STAT4 was over-expressed (P = 8.4 x 10(-5)) in cells carrying the risk haplotype for SLE compared with cells with a non-risk haplotype. The risk allele of the SNP rs7582694 in STAT4 correlated to production of anti-dsDNA (double-stranded DNA) antibodies and displayed a multiplicatively increased, 1.82-fold risk of SLE with two independent risk alleles of the IRF5 (interferon regulatory factor 5) gene.

  • 276.
    Sigurdsson, Snaevar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Göring, Harald
    Lindroos, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wiman, Ann-Christin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Sturfelt, Gunnar
    Jönsen, Andreas
    Rantapää-Dahlqvist, Solbritt
    Möller, Bozena
    Kere, Juha
    Koskenmies, Sari
    Widen, Elisabeth
    Eloranta, Maija-Leena
    Julkunen, Heikki
    Kristjansdottir, Helga
    Steinsson, Kristjan
    Alm, Gunnar
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupus Erythematosus2005In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, American Journal of Human Genetics, Vol. 76, no 3, p. 528-537Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease caused by both genetic and environmental factors. Genome scans in families with SLE point to multiple potential chromosomal regions that harbor SLE susceptibility genes, and association studies in different populations have suggested several susceptibility alleles for SLE. Increased production of type I interferon (IFN) and expression of IFN-inducible genes is commonly observed in SLE and may be pivotal in the molecular pathogenesis of the disease. We analyzed 44 single-nucleotide polymorphisms ( SNPs) in 13 genes from the type I IFN pathway in 679 Swedish, Finnish, and Icelandic patients with SLE, in 798 unaffected family members, and in 438 unrelated control individuals for joint linkage and association with SLE. In two of the genes - the tyrosine kinase 2 (TYK2) and IFN regulatory factor 5 (IRF5) genes - we identified SNPs that displayed strong signals in joint analysis of linkage and association (unadjusted P < 10(-7)) with SLE. TYK2 binds to the type I IFN receptor complex and IRF5 is a regulator of type I IFN gene expression. Thus, our results support a disease mechanism in SLE that involves key components of the type I IFN system.

  • 277.
    Sigurdsson, Snaevar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Padyukov, Leonid
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Alfredsson, Lars
    Rönnelid, Johan
    Klareskog, Lars
    Alm, Gunnar
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Polymorphisms in the Interferon Regulatory Factor 5 Gene are Associated with Anti-cyclic Citrullinated Peptide Antibody Negative Rheumatoid Arthritis2012Article in journal (Refereed)
  • 278.
    Smith, C. J. A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Oscarson, M.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Alimohammadi, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Perheentupa, J.
    Husebye, E. S.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Meloni, A.
    Crock, P. A.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Bensing, Sophie
    TSGA10-A Target for Autoantibodies in Autoimmune Polyendocrine Syndrome Type 1 and Systemic Lupus Erythematosus2011In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 73, no 2, p. 147-153Article in journal (Refereed)
    Abstract [en]

    Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High-titre autoantibodies are a characteristic feature of APS1 and are often associated with particular disease manifestations. Pituitary deficits are reported in approximately 7% of APS1 patients, with immunoreactivity to pituitary tissue frequently described. Using APS1 patient serum to immunoscreen a pituitary cDNA expression library, testis specific, 10 (TSGA10) was isolated. Immunoreactivity against TSGA10 was detected in 5/99 (5.05%) patients with APS1, but also in 5/135 (3.70%) systemic lupus erythematosus (SLE) patients and 1/188 (0.53%) healthy controls. TSGA10 autoantibodies were not detected in the serum from patients with any other autoimmune disease. Autoantibodies against TSGA10 were detectable from a young age in 4/5 positive APS1 patients with autoantibody titres remaining relatively constant over time. Furthermore, real-time PCR confirmed TSGA10 mRNA to be most abundantly expressed in the testis and also showed moderate and low expression levels throughout the entire body. TSGA10 should be considered as an autoantigen in a subset of APS1 patients and also in a minority of SLE patients. No recognizable clinical phenotype could be found to correlate with positive autoantibody reactivity.

  • 279.
    Sobol, Maria
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Klar, Joakim
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Laan, Loora
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Shahsavani, Mansoureh
    Karolinska Inst Solna, Dept Neurosci, Stockholm, Sweden.
    Schuster, Jens
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Annerén, Göran
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Konzer, Anne
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Dept Chem BMC Analyt Chem, Box 599, SE-75124 Uppsala, Sweden.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hoeber, Jan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Huss, Mikael
    Stockholm Univ, Natl Bioinformat Infrastruct Sweden, Sci Life Lab, Dept Biochem & Biophys, Solna, Sweden.
    Falk, Anna
    Karolinska Inst Solna, Dept Neurosci, Stockholm, Sweden.
    Dahl, Niklas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Transcriptome and Proteome Profiling of Neural Induced Pluripotent Stem Cells from Individuals with Down Syndrome Disclose Dynamic Dysregulations of Key Pathways and Cellular Functions2019In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 56, no 10, p. 7113-7127Article in journal (Refereed)
    Abstract [en]

    Down syndrome (DS) or trisomy 21 (T21) is a leading genetic cause of intellectual disability. To gain insights into dynamics of molecular perturbations during neurogenesis in DS, we established a model using induced pluripotent stem cells (iPSC) with transcriptome profiles comparable to that of normal fetal brain development. When applied on iPSCs with T21, transcriptome and proteome signatures at two stages of differentiation revealed strong temporal dynamics of dysregulated genes, proteins and pathways belonging to 11 major functional clusters. DNA replication, synaptic maturation and neuroactive clusters were disturbed at the early differentiation time point accompanied by a skewed transition from the neural progenitor cell stage and reduced cellular growth. With differentiation, growth factor and extracellular matrix, oxidative phosphorylation and glycolysis emerged as major perturbed clusters. Furthermore, we identified a marked dysregulation of a set of genes encoded by chromosome 21 including an early upregulation of the hub gene APP, supporting its role for disturbed neurogenesis, and the transcription factors OLIG1, OLIG2 and RUNX1, consistent with deficient myelination and neuronal differentiation. Taken together, our findings highlight novel sequential and differentiation-dependent dynamics of disturbed functions, pathways and elements in T21 neurogenesis, providing further insights into developmental abnormalities of the DS brain.

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  • 280. Song, Ci
    et al.
    Pedersen, Nancy L.
    Reynolds, Chandra A.
    Sabater-Lleal, Maria
    Kanoni, Stavroula
    Willenborg, Christina
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Watkins, Hugh
    Hamsten, Anders
    Prince, Jonathan A.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genetic Variants from Lipid-Related Pathways and Risk for Incident Myocardial Infarction2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 3, p. e60454-Article in journal (Refereed)
    Abstract [en]

    Background: Circulating lipids levels, as well as several familial lipid metabolism disorders, are strongly associated with initiation and progression of atherosclerosis and incidence of myocardial infarction (MI). Objectives: We hypothesized that genetic variants associated with circulating lipid levels would also be associated with MI incidence, and have tested this in three independent samples. Setting and Subjects: Using age- and sex-adjusted additive genetic models, we analyzed 554 single nucleotide polymorphisms (SNPs) in 41 candidate gene regions proposed to be involved in lipid-related pathways potentially predisposing to incidence of MI in 2,602 participants of the Swedish Twin Register (STR; 57% women). All associations with nominal P<0.01 were further investigated in the Uppsala Longitudinal Study of Adult Men (ULSAM; N = 1,142). Results: In the present study, we report associations of lipid-related SNPs with incident MI in two community-based longitudinal studies with in silico replication in a meta-analysis of genome-wide association studies. Overall, there were 9 SNPs in STR with nominal P-value <0.01 that were successfully genotyped in ULSAM. rs4149313 located in ABCA1 was associated with MI incidence in both longitudinal study samples with nominal significance (hazard ratio, 1.36 and 1.40; P-value, 0.004 and 0.015 in STR and ULSAM, respectively). In silico replication supported the association of rs4149313 with coronary artery disease in an independent meta-analysis including 173,975 individuals of European descent from the CARDIoGRAMplusC4D consortium (odds ratio, 1.03; P-value, 0.048). Conclusions: rs4149313 is one of the few amino acid changing variants in ABCA1 known to associate with reduced cholesterol efflux. Our results are suggestive of a weak association between this variant and the development of atherosclerosis and MI.

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  • 281. Sovio, Ulla
    et al.
    Mook-Kanamori, Dennis O.
    Warrington, Nicole M.
    Lawrence, Robert
    Briollais, Laurent
    Palmer, Colin N. A.
    Cecil, Joanne
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Kaakinen, Marika
    Beilin, Lawrie J.
    Millwood, Iona Y.
    Bennett, Amanda J.
    Laitinen, Jaana
    Pouta, Anneli
    Molitor, John
    Smith, George Davey
    Ben-Shlomo, Yoav
    Jaddoe, Vincent W. V.
    Palmer, Lyle J.
    Pennell, Craig E.
    Cole, Tim J.
    McCarthy, Mark I.
    Järvelin, Marjo-Riitta
    Timpson, Nicholas J.
    Association between Common Variation at the FTO Locus and Changes in Body Mass Index from Infancy to Late Childhood: The Complex Nature of Genetic Association through Growth and Development2011In: PLoS Genetics, ISSN 1553-7390, Vol. 7, no 2, p. e1001307-Article in journal (Refereed)
    Abstract [en]

    An age-dependent association between variation at the FTO locus and BMI in children has been suggested. We meta-analyzed associations between the FTO locus (rs9939609) and BMI in samples, aged from early infancy to 13 years, from 8 cohorts of European ancestry. We found a positive association between additional minor (A) alleles and BMI from 5.5 years onwards, but an inverse association below age 2.5 years. Modelling median BMI curves for each genotype using the LMS method, we found that carriers of minor alleles showed lower BMI in infancy, earlier adiposity rebound (AR), and higher BMI later in childhood. Differences by allele were consistent with two independent processes: earlier AR equivalent to accelerating developmental age by 2.37% (95% CI 1.87, 2.87, p = 10−20) per A allele and a positive age by genotype interaction such that BMI increased faster with age (p = 10−23). We also fitted a linear mixed effects model to relate genotype to the BMI curve inflection points adiposity peak (AP) in infancy and AR. Carriage of two minor alleles at rs9939609 was associated with lower BMI at AP (−0.40% (95% CI: −0.74, −0.06), p = 0.02), higher BMI at AR (0.93% (95% CI: 0.22, 1.64), p = 0.01), and earlier AR (−4.72% (−5.81, −3.63), p = 10−17), supporting cross-sectional results. Overall, we confirm the expected association between variation at rs9939609 and BMI in childhood, but only after an inverse association between the same variant and BMI in infancy. Patterns are consistent with a shift on the developmental scale, which is reflected in association with the timing of AR rather than just a global increase in BMI. Results provide important information about longitudinal gene effects and about the role of FTO in adiposity. The associated shifts in developmental timing have clinical importance with respect to known relationships between AR and both later-life BMI and metabolic disease risk.

  • 282. Strawbridge, Rona J.
    et al.
    Dupuis, Josee
    Prokopenko, Inga
    Barker, Adam
    Ahlqvist, Emma
    Rybin, Denis
    Petrie, John R.
    Travers, Mary E.
    Bouatia-Naji, Nabila
    Dimas, Antigone S.
    Nica, Alexandra
    Wheeler, Eleanor
    Chen, Han
    Voight, Benjamin F.
    Taneera, Jalal
    Kanoni, Stavroula
    Peden, John F.
    Turrini, Fabiola
    Gustafsson, Stefan
    Zabena, Carina
    Almgren, Peter
    Barker, David J. P.
    Barnes, Daniel
    Dennison, Elaine M.
    Eriksson, Johan G.
    Eriksson, Per
    Eury, Elodie
    Folkersen, Lasse
    Fox, Caroline S.
    Frayling, Timothy M.
    Goel, Anuj
    Gu, Harvest F.
    Horikoshi, Momoko
    Isomaa, Bo
    Jackson, Anne U.
    Jameson, Karen A.
    Kajantie, Eero
    Kerr-Conte, Julie
    Kuulasmaa, Teemu
    Kuusisto, Johanna
    Loos, Ruth J. F.
    Luan, Jian'an
    Makrilakis, Konstantinos
    Manning, Alisa K.
    Teresa Martinez-Larrad, Maria
    Narisu, Narisu
    Mannila, Maria Nastase
    Ohrvik, John
    Osmond, Clive
    Pascoe, Laura
    Payne, Felicity
    Sayer, Avan A.
    Sennblad, Bengt
    Silveira, Angela
    Stancakova, Alena
    Stirrups, Kathy
    Swift, Amy J.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tuomi, Tiinamaija
    van 't Hooft, Ferdinand M.
    Walker, Mark
    Weedon, Michael N.
    Xie, Weijia
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ongen, Halit
    Malarstig, Anders
    Hopewell, Jemma C.
    Saleheen, Danish
    Chambers, John
    Parish, Sarah
    Danesh, John
    Kooner, Jaspal
    Ostenson, Claes-Goran
    Lind, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Cooper, Cyrus C.
    Serrano-Rios, Manuel
    Ferrannini, Ele
    Forsen, Tom J.
    Clarke, Robert
    Franzosi, Maria Grazia
    Seedorf, Udo
    Watkins, Hugh
    Froguel, Philippe
    Johnson, Paul
    Deloukas, Panos
    Collins, Francis S.
    Laakso, Markku
    Dermitzakis, Emmanouil T.
    Boehnke, Michael
    McCarthy, Mark I.
    Wareham, Nicholas J.
    Groop, Leif
    Pattou, Francois
    Gloyn, Anna L.
    Dedoussis, George V.
    Lyssenko, Valeriya
    Meigs, James B.
    Barroso, Ines
    Watanabe, Richard M.
    Ingelsson, Erik
    Langenberg, Claudia
    Hamsten, Anders
    Florez, Jose C.
    Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes2011In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 10, p. 2624-2634Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE-Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired beta-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS-We have conducted a meta-analysis of genome-wide association tests of similar to 2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS-Nine SNPs at eight loci were associated with proinsulin levels (P < 5 x 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC3OA8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 x 10(-4)), improved beta-cell function (P = 1.1 x 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 x 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS-We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis. 

  • 283.
    Strawbridge, Rona J.
    et al.
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Hilding, Agneta
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Silveira, Angela
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Österholm, Cecilia
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Nova Southeastern Univ, Cell Therapy Inst, Ft Lauderdale, FL USA..
    Sennblad, Bengt
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Inst, Sci Life Lab, Stockholm, Sweden..
    McLeod, Olga
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Tsikrika, Panagiota
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Foroogh, Fariba
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Tremoli, Elena
    Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy.;Ist Ricovero & Cura Carattere Sci, Ctr Cardiol Monzino, Milan, Italy..
    Baldassarre, Damiano
    Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy.;Ist Ricovero & Cura Carattere Sci, Ctr Cardiol Monzino, Milan, Italy..
    Veglia, Fabrizio
    Ist Ricovero & Cura Carattere Sci, Ctr Cardiol Monzino, Milan, Italy..
    Rauramaa, Rainer
    Fdn Res Hlth Exercise & Nutr, Kuopio Res Inst Exercise Med, Kuopio, Finland.;Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, Kuopio, Finland..
    Smit, Andries J.
    Univ Med Ctr Groningen, Dept Med, Groningen, Netherlands..
    Giral, Phillipe
    Grp Hosp Pitie Salpetriere, Assistance Publ Hop Paris, Serv Endocrinol Metab, Unites Prevent Cardiovasc, Paris, France..
    Kurl, Sudhir
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio Campus, Kuopio, Finland..
    Mannarino, Elmo
    Univ Perugia, Dept Clin & Expt Med, Internal Med Angiol & Arteriosclerosis Dis, Perugia, Italy..
    Grossi, Enzo
    Bracco Med Dept, Milan, Italy..
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Humphries, Steve E.
    UCL, Ctr Cardiovasc Genet, London, England..
    de Faire, Ulf
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Östenson, Claes-Goran
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Maegdefessel, Lars
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Backlund, Alexandra
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Soluble CD93 Is Involved in Metabolic Dysregulation but Does Not Influence Carotid Intima-Media Thickness2016In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, no 10, p. 2888-2899Article in journal (Refereed)
    Abstract [en]

    Type 2 diabetes and cardiovascular disease are complex disorders involving metabolic and inflammatory mechanisms. Here we investigated whether sCD93, a group XIV c-type lectin of the endosialin family, plays a role in metabolic dysregulation or carotid intima-media thickness (IMT). Although no association was observed between sCD93 and IMT, sCD93 levels were significantly lower in subjects with type 2 diabetes (n = 901, mean 6 SD 156.6 +/- 40.0 ng/mL) compared with subjects without diabetes (n = 2,470, 164.1 +/- 44.8 ng/mL, P < 0.0001). Genetic variants associated with diabetes risk (DIAGRAM Consortium) did not influence sCD93 levels (individually or combined in a single nucleotide polymorphism score). In a prospective cohort, lower sCD93 levels preceded the development of diabetes. Consistent with this, a cd93-deficient mouse model (in addition to apoe deficiency) demonstrated no difference in atherosclerotic lesion development compared with apoe(-/-) cd93-sufficient littermates. However, cd93-deficient mice showed impaired glucose clearance and insulin sensitivity (compared with littermate controls) after eating a high-fat diet. The expression of cd93 was observed in pancreatic islets, and leaky vessels were apparent in cd93-deficient pancreases. We further demonstrated that stress-induced release of sCD93 is impaired by hyperglycemia. Therefore, we propose CD93 as an important component in glucometabolic regulation.

  • 284.
    Strawbridge, Rona J.
    et al.
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Univ Glasgow, Inst Mental Hlth & Wellbeing, Mental Hlth & Wellbeing, Glasgow, Lanark, Scotland.;Univ Glasgow, Dept Hlth & Wellbeing, Glasgow G12 8RZ, Lanark, Scotland..
    Silveira, Angela
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    den Hoed, Marcel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gustafsson, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Luan, Jian'an
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England..
    Rybin, Denis
    Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA..
    Dupuis, Josee
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA.;Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA..
    Li-Gao, Ruifang
    Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden, Netherlands..
    Kavousi, Maryam
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Dehghan, Abbas
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, London, England..
    Haljas, Kadri
    Univ Helsinki, Fac Med, Dept Psychol & Logoped, Helsinki, Finland..
    Lahti, Jari
    Univ Helsinki, Fac Med, Dept Psychol & Logoped, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland..
    Gadin, Jesper R.
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Backlund, Alexandra
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    de Faire, Ulf
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Gertow, Karl
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Giral, Phillipe
    Grp Hosp Pitie Salpetriere, AP HP, Serv Endocrinol Metab, Unites Prevent Cardiovasc, Paris, France..
    Goel, Anuj
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England..
    Humphries, Steve E.
    UCL, Inst Cardiovasc Sci, Ctr Cardiovasc Genet, London, England..
    Kurl, Sudhir
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio Campus, Kuopio, Finland..
    Langenberg, Claudia
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England.;Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, London, England..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England.;Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, London, England..
    Lindgren, Cecilia C. M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Mannarino, Elmo
    Univ Perugia, Dept Clin & Expt Med Internal Med Angiol & Arteri, Perugia, Italy..
    Mook-Kanamori, Dennis O.
    Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, Leiden, Netherlands..
    Morris, Andrew P.
    Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England..
    de Mutsert, Renee
    Univ Helsinki, Fac Med, Dept Psychol & Logoped, Helsinki, Finland..
    Rauramaa, Rainer
    Kuopio Res Inst Exercise Med, Fdn Res Hlth Exercise & Nutr, Kuopio, Finland.;Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, Kuopio, Finland..
    Saliba-Gustafsson, Peter
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Sennblad, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.
    Smit, Andries J.
    Univ Med Ctr Groningen, Dept Med, Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Med, Groningen, Netherlands..
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tremoli, Elena
    Univ Milan, Dipartimento Sci Farmacolog & Biomol, Milan, Italy.;IRCCS, Ctr Cardiolog Monzino, Milan, Italy..
    Veglia, Fabrizio
    IRCCS, Ctr Cardiolog Monzino, Milan, Italy..
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bjorck, Hanna M.
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Eriksson, Johan G.
    Folkhalsan Res Ctr, Helsinki, Finland.;Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland.;Natl Inst Hlth & Welf, Helsinki, Finland..
    Hofman, Albert
    Harvard T H Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA..
    Franco, Oscar H.
    Watkins, Hugh
    Jukema, J. Wouter
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands.;Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands..
    Florez, Jose C.
    Massachusetts Gen Hosp, Diabet Unit, Boston, MA USA.;Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA USA.;Broad Inst, Programs Metab & Med & Populat Genet, Cambridge, MA USA.;Harvard Med Sch, Dept Med, Cambridge, MA USA..
    Wareham, Nicholas J.
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England..
    Meigs, James B.
    Broad Inst, Programs Metab & Med & Populat Genet, Cambridge, MA USA.;Harvard Med Sch, Dept Med, Cambridge, MA USA.;Massachusetts Gen Hosp, Gen Med Div, Boston, MA USA..
    Ingelsson, Erik
    Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, CA USA..
    Baldassarre, Damiano
    Univ Milan, Dipartimento Sci Farmacolog & Biomol, Milan, Italy.;Univ Milan, Dept Med Biotechnol & Translat Med, Milan, Italy..
    Hamsten, Anders
    Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation2017In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 266, p. 196-204Article in journal (Refereed)
    Abstract [en]

    Background and aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling.

    Methods: We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants.

    Results: We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures.

    Conclusions: We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT.

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  • 285.
    Stålberg, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Wang, Shu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Larsson, Catharina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Weber, Günther
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Gobl, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Suppression of the neoplastic phenotype by transfection of phospholipase C3 to neuroendocrine tumor cells1999In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 450, no 3, p. 210-216Article in journal (Refereed)
    Abstract [en]

    The expression of phospholipase C beta 3 (PLCB3) is low or absent in several neuroendocrine neoplasias. To investigate the role of PLCB3 in the neuroendocrine tumorigenesis, we transfected a PLCB3 construct to three neuroendocrine tumor cell lines with a low PLCB3 expression. The growth rate and tumorigenicity were assessed in vitro by [3H]thymidine incorporation and cell counting, in vivo, by xenografting to nude mice. In vitro, PLCB3 expressing clones showed a significant growth inhibition. The tumor weight was reduced for one of the two xenografted PLCB3-transfected cell lines and in both, a reduced number of proliferating (Ki-67 positive) cells was observed. This study implies an essential role for PLCB3 in the neuroendocrine tumorigenesis.

  • 286. Surakka, Ida
    et al.
    Whitfield, John B
    Perola, Markus
    Visscher, Peter M
    Montgomery, Grant W
    Falchi, Mario
    Willemsen, Gonneke
    de Geus, Eco J C
    Magnusson, Patrik K E
    Christensen, Kaare
    Sørensen, Thorkild I A
    Pietiläinen, Kirsi H
    Rantanen, Taina
    Silander, Kaisa
    Widén, Elisabeth
    Muilu, Juha
    Rahman, Iffat
    Liljedahl, Ulrika
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Palotie, Aarno
    Kaprio, Jaakko
    Kyvik, Kirsten O
    Pedersen, Nancy L
    Boomsma, Dorret I
    Spector, Tim
    Martin, Nicholas G
    Ripatti, Samuli
    Peltonen, Leena
    A Genome-Wide Association Study of Monozygotic Twin-Pairs Suggests a Locus Related to Variability of Serum High-Density Lipoprotein Cholesterol2012In: Twin Research and Human Genetics, ISSN 1832-4274, E-ISSN 1839-2628, Vol. 15, no 6, p. 691-699Article in journal (Refereed)
    Abstract [en]

    Genome-wide association analysis on monozygotic twin-pairs offers a route to discovery of gene-environment interactions through testing for variability loci associated with sensitivity to individual environment/lifestyle. We present a genome-wide scan of loci associated with intra-pair differences in serum lipid and apolipoprotein levels. We report data for 1,720 monozygotic female twin-pairs from GenomEUtwin project with 2.5 million SNPs, imputed or genotyped, and measured serum lipid fractions for both twins. We found one locus associated with intra-pair differences in high-density lipoprotein cholesterol, rs2483058 in an intron of SRGAP2, where twins carrying the C allele are more sensitive to environmental factors (P = 3.98 × 10-8). We followed up the association in further genotyped monozygotic twins (N = 1,261), which showed a moderate association for the variant (P = 0.200, same direction of an effect). In addition, we report a new association on the level of apolipoprotein A-II (P = 4.03 × 10-8).

  • 287.
    Svensson, Emma
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution.
    Günther, Torsten
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution.
    Hoischen, Alexander
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6526 Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6526 Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis RCI, NL-6526 Nijmegen, Netherlands..
    Hervella, Montserrat
    Univ Basque Country, UPV EHU, Fac Sci & Technol, Dept Genet Phys Anthropol & Anim Physiol, B Sarriena S-N, Leioa 48940, Bizkaia, Spain..
    Munters, Arielle
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ioana, Mihai
    Univ Med & Pharm, Lab Human Genet, Craiova, Romania..
    Ridiche, Florin
    Oltenia Museum Craiova, Craiova, Romania..
    Edlund, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution.
    van Deuren, Rosanne C.
    Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6526 Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis RCI, NL-6526 Nijmegen, Netherlands..
    Soficaru, Andrei
    Romanian Acad, Francisc J Rainer Inst Anthropol, Bucharest 050474, Romania..
    De-la-Rua, Concepcion
    Univ Basque Country, UPV EHU, Fac Sci & Technol, Dept Genet Phys Anthropol & Anim Physiol, B Sarriena S-N, Leioa 48940, Bizkaia, Spain..
    Netea, Mihai G.
    Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6526 Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis RCI, NL-6526 Nijmegen, Netherlands.;Univ Med & Pharm, Lab Human Genet, Craiova, Romania..
    Jakobsson, Mattias
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution.
    Genome of Pesxtera Muierii skull shows high diversity and low mutational load in pre-glacial Europe2021In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 31, no 14, p. 2973-U21Article in journal (Refereed)
    Abstract [en]

    Few complete human genomes from the European Early Upper Palaeolithic (EUP) have been sequenced. Using novel sampling and DNA extraction approaches, we sequenced the genome of a woman from "Pesxtera Muierii,"Romania who lived similar to 34,000 years ago to 13.5x coverage. The genome shows similarities to modern-day Europeans, but she is not a direct ancestor. Although her cranium exhibits both modern human and Neanderthal features, the genome shows similar levels of Neanderthal admixture (similar to 3.1%) to most EUP humans but only half compared to the similar to 40,000-year-old Pesxtera Oase 1. All EUP European hunter-gatherers display high genetic diversity, demonstrating that the severe loss of diversity occurred during and after the Last Glacial Maximum (LGM) rather than just during the out-of-Africa migration. The prevalence of genetic diseases is expected to increase with low diversity; however, pathogenic variant load was relatively constant from EUP to modern times, despite post-LGM hunter-gatherers having the lowest diversity ever observed among Europeans.

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  • 288. Svenungsson, Elisabet
    et al.
    Gustafsson, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sandling, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Gunnarsson, Iva
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jönsen, Andreas
    Bengtsson, Anders A
    Sturfelt, Gunnar
    Rantapää-Dahlqvist, Solbritt
    Elvin, Kerstin
    Sundin, Ulf
    Garnier, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Simard, Julia F
    Sigurdsson, Snaevar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Padyukov, Leonid
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    A STAT4 risk allele is associated with ischaemic cerebrovascular events and anti-phospholipid antibodies in systemic lupus erythematosus2010In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 69, no 5, p. 834-840Article in journal (Refereed)
    Abstract [en]

    Objective

    To investigate whether the risk allele for systemic lupus erythematosus (SLE) in the signal transducer and activator of transcription factor 4 (STAT4) gene, defined by the single nucleotide polymorphism (SNP) rs10181656(G), is associated with vascular events and/or presence of prothrombotic anti-phospholipid antibodies (aPL) in patients with SLE.

    Methods

    Two independent groups of unrelated patients with SLE of Swedish ethnicity (n=424 and 154) were genotyped, and occurrence of previous manifestations of ischaemic heart disease (IHD), ischaemic cerebrovascular disease (ICVD) and venous thromboembolic events (VTE) was tabulated. aPL values were measured by ELISA. Matched controls (n=492 and 194) were genotyped.

    Results

    The STAT4 risk allele was more frequent in patients with SLE with previous arterial events (combined OR (ORc)=1.5, 95% CI 1.1 to 2.0) compared to patients without such events. The association was mainly attributable to an accumulation of the risk allele among patients with ICVD (ORc=2.3, CI 1.6 to 3.3). There was no association with IHD or VTE. The presence of two or more aPLs was associated with the risk allele (ORc=1.6, 95% CI 1.2 to 2.0). In multivariable-adjusted logistic regression analyses treatment for hypertension, at least one STAT4 risk allele, older age, IgG anti-cardiolipin antibodies and longer SLE duration remained independently associated with previous ICVD (p≤0.02 for all).

    Conclusion

    Patients with SLE with the STAT4 risk allele had a strikingly increased risk of ICVD, comparable in magnitude to that of hypertension. The results imply that a genetic predisposition is an important and previously unrecognised risk factor for ICVD in SLE, and that aPLs may be one underlying mechanism.

  • 289.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    From gels to chips: "Minisequencing" primer extension for analysis of point mutations and single nucleotide polymorphisms1999In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 13, no 1, p. 1-10Article in journal (Refereed)
    Abstract [en]

    In the minisequencing primer extension reaction, a DNA polymerase is used specifically to extend a primer that anneals immediately adjacent to the nucleotide position to be analyzed with a single labeled nucleoside triphospate complementary to the nucleotide at the variant site. The reaction allows highly specific detection of point mutations and single nucleotide polymorphisms (SNPs). Because all SNPs can be analyzed with high specificty at the same reaction conditions, minisequencing is a promising reaction principle for multiplex high-throughput genotyping assays. It is also a useful tool for accurate quantitative PCR-based analysis. This review discusses the different approaches, ranging from traditional gel-based formats to multiplex detection on microarrays that have been developed and applied to minisequencing assays.

  • 290.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Microarrays: Use in Mutation Detection2003In: Nature encyclopedia of the human genome / [ed] David N. Cooper, London: Nature Publishing Group, 2003, 5 vol, p. 940-944Chapter in book (Other (popular science, discussion, etc.))
  • 291.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Toward genome-wide SNP genotyping2005In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 37 Suppl, p. S5-S10Article in journal (Other academic)
    Abstract [en]

    Genome-wide association studies with SNP markers are expected to allow identification of genes that underlie complex disorders. Hundreds of thousands of SNP markers will be required for comprehensive genome-wide association studies. The development of microarray-based methods for SNP genotyping on this scale remains a demanding task, despite many recent advances in technology for the production of high-density microarrays. A key technical obstacle is the PCR amplification step, which is required to reduce the complexity of and gain sufficient sensitivity for genotyping SNPs in large, diploid genomes. The multiplexing level that can be achieved in PCR does not match that of current microarray-based methods, making PCR the limiting step in the assays. Highly multiplexed microarray systems for SNP genotyping have recently been developed by combining well-known reaction principles for DNA amplification and SNP genotyping in clever ways. These new methods offer the potential of genome-wide SNP mapping of genes involved in complex diseases in the foreseeable future, provided that issues related to selection of the optimal SNP markers, sample throughput and the cost of the assays can be addressed.

  • 292.
    Syvänen, Ann-Christine
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Söderlund, Hans
    DNA sandwiches with silver and gold2002In: Nature Biotechnology, ISSN 1087-0156, E-ISSN 1546-1696, Vol. 20, no 4, p. 349-350Article in journal (Other academic)
  • 293.
    Syvänen, Ann-Christine
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Taylor, Graham R
    Approaches for analyzing human mutations and nucleotide sequence variation: a report from the Seventh International Mutation Detection meeting, 20032004In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 23, no 5, p. 401-405Article in journal (Other academic)
    Abstract [en]

    The Seventh International Symposium on Mutations in the Human Genome, Mutation Detection 2003, was held during 2–6 July 2003 in Palm Cove near Cairns, Australia. The meeting was organized under the auspices of the Human Genome Organisation (HUGO) as a satellite meeting of the International World Congress of Genetics, held in Melbourne the following week. Meeting participants reported on advances in mutation detection technologies, including advances in high-throughput detection systems for SNP genotyping applicable to the international haplotype mapping project (HapMap); and bioinformatics tools, including databases for handling and processing growing amounts of genome variation data.

  • 294.
    Sætre, Glenn-Peter
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Evolutionary Biology.
    Borge, Thomas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Evolutionary Biology.
    Lindroos, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Haavie, Jon
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Evolutionary Biology.
    Sheldon, Ben C
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology.
    Primmer, Craig
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Sex chromosome evolution and speciation in Ficedula flycatchers2003In: Proceedings of the Royal Society of London. Biological Sciences, ISSN 0962-8452, E-ISSN 1471-2954, Vol. 270, no 1510, p. 53-59Article in journal (Other academic)
    Abstract [en]

    Speciation is the combination of evolutionary processes that leads to the reproductive isolation of different populations. We investigate the significance of sex-chromosome evolution on the development of post- and prezygotic isolation in two naturally hybridizing Ficedula flycatcher species. Applying a tag-array-based mini-sequencing assay to genotype single nucleotide polymorphisms (SNPs) and interspecific substitutions, we demonstrate rather extensive hybridization and backcrossing in sympatry. However, gene flow across the partial postzygotic barrier (introgression) is almost exclusively restricted to autosomal loci, suggesting strong selection against introgression of sex-linked genes. In addition to this partial postzygotic barrier, character displacement of male plumage characteristics has previously been shown to reinforce prezygotic isolation in these birds. We show that male plumage traits involved in reinforcing prezygotic isolation are sex linked. These results suggest a major role of sex-chromosome evolution in mediating post- and prezygotic barriers to gene flow and point to a causal link in the development of the two forms of reproductive isolation.

  • 295. 't Hoen, Peter A C
    et al.
    Friedländer, Marc R
    Almlöf, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sammeth, Michael
    Pulyakhina, Irina
    Anvar, Seyed Yahya
    Laros, Jeroen F J
    Buermans, Henk P J
    Karlberg, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Brännvall, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    den Dunnen, Johan T
    van Ommen, Gert-Jan B
    Gut, Ivo G
    Guigó, Roderic
    Estivill, Xavier
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dermitzakis, Emmanouil T
    Lappalainen, Tuuli
    Reproducibility of high-throughput mRNA and small RNA sequencing across laboratories2013In: Nature Biotechnology, ISSN 1087-0156, E-ISSN 1546-1696, Vol. 31, no 11, p. 1015-1022Article in journal (Refereed)
    Abstract [en]

    RNA sequencing is an increasingly popular technology for genome-wide analysis of transcript sequence and abundance. However, understanding of the sources of technical and interlaboratory variation is still limited. To address this, the GEUVADIS consortium sequenced mRNAs and small RNAs of lymphoblastoid cell lines of 465 individuals in seven sequencing centers, with a large number of replicates. The variation between laboratories appeared to be considerably smaller than the already limited biological variation. Laboratory effects were mainly seen in differences in insert size and GC content and could be adequately corrected for. In small-RNA sequencing, the microRNA (miRNA) content differed widely between samples owing to competitive sequencing of rRNA fragments. This did not affect relative quantification of miRNAs. We conclude that distributing RNA sequencing among different laboratories is feasible, given proper standardization and randomization procedures. We provide a set of quality measures and guidelines for assessing technical biases in RNA-seq data.

  • 296.
    Tasa, Tonis
    et al.
    Univ Tartu, Inst Comp Sci, EE-50409 Tartu, Estonia;Univ Tartu, Inst Genom, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
    Krebs, Kristi
    Univ Tartu, Inst Genom, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
    Kals, Mart
    Univ Tartu, Inst Genom, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
    Mägi, Reedik
    Univ Tartu, Inst Genom, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
    Lauschke, Volker M.
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Pharmacogenet, S-17177 Stockholm, Sweden.
    Haller, Toomas
    Univ Tartu, Inst Genom, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
    Puurand, Tarmo
    Univ Tartu, Inst Mol & Cell Biol, Dept Bioinformat, EE-51010 Tartu, Estonia.
    Remm, Maido
    Univ Tartu, Inst Mol & Cell Biol, Dept Bioinformat, EE-51010 Tartu, Estonia.
    Esko, Tonu
    Univ Tartu, Inst Genom, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
    Metspalu, Andres
    Univ Tartu, Inst Genom, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
    Vilo, Jaak
    Univ Tartu, Inst Comp Sci, EE-50409 Tartu, Estonia.
    Milani, Lili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Tartu, Inst Genom, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
    Genetic variation in the Estonian population: pharmacogenomics study of adverse drug effects using electronic health records2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, no 3, p. 442-454Article in journal (Refereed)
    Abstract [en]

    Pharmacogenomics aims to tailor pharmacological treatment to each individual by considering associations between genetic polymorphisms and adverse drug effects (ADEs). With technological advances, pharmacogenomic research has evolved from candidate gene analyses to genome-wide association studies. Here, we integrate deep whole-genome sequencing (WGS) information with drug prescription and ADE data from Estonian electronic health record (EHR) databases to evaluate genome- and pharmacome-wide associations on an unprecedented scale. We leveraged WGS data of 2240 Estonian Biobank participants and imputed all single-nucleotide variants (SNVs) with allele counts over 2 for 13,986 genotyped participants. Overall, we identified 41 (10 novel) loss-of-function and 567 (134 novel) missense variants in 64 very important pharmacogenes. The majority of the detected variants were very rare with frequencies below 0.05%, and 6 of the novel lossof-function and 99 of the missense variants were only detected as single alleles (allele count = 1). We also validated documented pharmacogenetic associations and detected new independent variants in known gene-drug pairs. Specifically, we found that CTNNA3 was associated with myositis and myopathies among individuals taking nonsteroidal anti-inflammatory oxicams and replicated this finding in an extended cohort of 706 individuals. These findings illustrate that population-based WGS-coupled EHRs are a useful tool for biomarker discovery.

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  • 297.
    Tay, Nicole
    et al.
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Macare, Christine
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Liu, Yun
    Fudan Univ, Dept Biochem & Mol Biol, MOE Key Lab Metab & Mol Med, Sch Basic Med Sci, Shanghai, Peoples R China.
    Ruggeri, Barbara
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Jia, Tianye
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England;Fudan Univ, Inst Sci & Technol Brain Inspired Intelligen, Shanghai, Peoples R China;Fudan Univ, Key Lab Computat Neurosci & Brain Inspired Intell, Minist Educ, Shanghai, Peoples R China.
    Chu, Congying
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Biondo, Francesca
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Ing, Alex
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Luo, Qiang
    Fudan Univ, Sch Life Sci, Shanghai, Peoples R China;Fudan Univ, Inst Sci & Technol Brain Inspired Intelligence, Shanghai, Peoples R China.
    Sarkisyan, Daniil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Banaschewski, Tobias
    Heidelberg Univ, Dept Child & Adolescent Psychiat & Psychotherapy, Cent Inst Mental Hlth, Mannheim, Germany.
    Barker, Gareth J.
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Bokde, Arun L. W.
    Trinity Coll Dublin, Discipline Psychiat, Sch Med, Dublin, Ireland;Trinity Coll Dublin, Trinity Coll, Inst Neurosci, Dublin, Ireland.
    Bromberg, Uli
    Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany.
    Büchel, Christian
    Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany.
    Quinlan, Erin Burke
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Desrivieres, Sylvane
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Flor, Herta
    Heidelberg Univ, Dept Cognit & Clin Neurosci, Cent Inst Mental Hlth, Med Fac Mannheim, Mannheim, Germany;Univ Mannheim, Dept Psychol, Sch Social Sci, Mannheim, Germany.
    Frouin, Vincent
    Univ Paris Saclay, NeuroSpin, Gif Sur Yvette, France.
    Garavan, Hugh
    Univ Vermont, Dept Psychiat, Burlington, VT USA;Univ Vermont, Dept Psychol, Burlington, VT 05405 USA.
    Gowland, Penny
    Univ Nottingham, Sir Peter Mansfield Imaging Ctr Sch Phys, Nottingham, England.
    Heinz, Andreas
    Univ Med Berlin, Charite, Dept Psychiat & Psychotherapy, Campus Charite Mitte, Berlin, Germany.
    Ittermann, Bernd
    Phys Tech Bundesanstalt, Berlin, Germany.
    Martinot, Jean-Luc
    Univ Paris 05, Univ Paris Sud Paris Saclay, Unit 1000 Neuroimaging & Psychiat, DIGITEO Labs,INSERM, Gif Sur Yvette, France;Cochin Hosp, Maison Solenn, Paris, France.
    Artiges, Eric
    Univ Paris Saclay, Univ Paris Sud, DIGITEO Labs, INSERM, Gif Sur Yvette, France;Orsay Hosp, Dept Psychiat, Orsay, France.
    Nees, Frauke
    Trinity Coll Dublin, Discipline Psychiat, Sch Med, Dublin, Ireland;Trinity Coll Dublin, Trinity Coll, Inst Neurosci, Dublin, Ireland;Heidelberg Univ, Dept Cognit & Clin Neurosci, Cent Inst Mental Hlth, Med Fac Mannheim, Mannheim, Germany;Heidelberg Univ, Dept Child & Adolescent Psychiat & Psychotherapy, Cent Inst Mental Hlth, Med Fac Mannheim, Mannheim, Germany;Nees German Res Fdn, Bonn, Germany.
    Orfanos, Dimitri Papadopoulos
    Univ Paris Saclay, NeuroSpin, Gif Sur Yvette, France.
    Paus, Tomas
    Univ Toronto, Bloorview Res Inst, Holland Bloorview Kids Rehabil, Hosp & Dept Psychol, Toronto, ON, Canada;Univ Toronto, Bloorview Res Inst, Holland Bloorview Kids Rehabil, Dept Psychiat, Toronto, ON, Canada.
    Poustka, Luise
    Univ Med Ctr Gottingen, Dept Child & Adolescent Psychiat & Psychotherapy, Gottingen, Germany;Med Univ Vienna, Clin Child & Adolescent Psychiat, Vienna, Austria.
    Hohmann, Sarah
    Heidelberg Univ, Dept Child & Adolescent Psychiat & Psychotherapy, Cent Inst Mental Hlth, Mannheim, Germany.
    Fröhner, Juliane H.
    Tech Univ Dresden, Dept Psychiat, Dresden, Germany;Tech Univ Dresden, Neuroimaging Ctr, Dresden, Germany.
    Smolka, Michael N.
    Tech Univ Dresden, Dept Psychiat, Dresden, Germany;Tech Univ Dresden, Neuroimaging Ctr, Dresden, Germany.
    Walter, Henrik
    Univ Med Berlin, Charite, Dept Psychiat & Psychotherapy, Campus Charite Mitte, Berlin, Germany.
    Whelan, Robert
    Trinity Coll Dublin, Sch Psychol, Dublin, Ireland;Trinity Coll Dublin, Global Brain Hlth Inst, Dublin, Ireland.
    Frieling, Helge
    Hannover Med Sch, Dept Psychiat Social Psychiat & Psychotherapy, Hannover, Germany.
    Bleich, Stefan
    Hannover Med Sch, Dept Psychiat Social Psychiat & Psychotherapy, Hannover, Germany.
    Barker, Edward D.
    Kings Coll London, Ctr Neuroimaging Sci, Inst Psychiat Psychol & Neurosci, London, England.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rüegg, Joelle
    Karolinska Inst, Dept Clin Neurosci, Ctr Mol Med, Stockholm, Sweden.
    Ekström, Tomas J.
    Karolinska Inst, Dept Clin Neurosci, Ctr Mol Med, Stockholm, Sweden.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schumann, Gunter
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Allele-Specific Methylation of SPDEF: A Novel Moderator of Psychosocial Stress and Substance Abuse2019In: American Journal of Psychiatry, ISSN 0002-953X, E-ISSN 1535-7228, Vol. 176, no 2, p. 146-155Article in journal (Refereed)
    Abstract [en]

    Objective: Psychosocial stress is a key risk factor for substance abuse among adolescents. Recently, epigenetic processes such as DNA methylation have emerged as potential mechanisms that could mediate this relationship. The authors conducted a genome-wide methylation analysis to investigate whether differentially methylated regions are associated with psychosocial stress in an adolescent population.

    Methods: A methylome-wide analysis of differentially methylated regions was used to examine a sample of 1,287 14-year-old adolescents (50.7% of them female) from the European IMAGEN study. The Illumina 450k array was used to assess DNA methylation, pyrosequencing was used for technical replication, and linear regression analyses were used to identify associations with psychosocial stress and substance use (alcohol and tobacco). Findings were replicated by pyrosequencing a test sample of 413 participants from the IMAGEN study.

    Results: Hypermethylation in the sterile alpha motif/pointed domain containing the ETS transcription factor (SPDEF) gene locus was associated with a greater number of stressful life events in an allele-dependent way. Among individuals with the minor G-allele, SPDEF methylation moderated the association between psychosocial stress and substance abuse. SPDEF methylation interacted with lifetime stress in gray matter volume in the right cuneus, which in turn was associated with the frequency of alcohol and tobacco use. SPDEF was involved in the regulation of trans-genes linked to substance use.

    Conclusions: Taken together, the study findings describe a novel epigenetic mechanism that helps explain how psychosocial stress exposure influences adolescent substance abuse.

  • 298.
    Teppo, Susanna
    et al.
    Univ Tampere, Tampere Ctr Child Hlth Res, Tampere 33520, Finland.;Tampere Univ Hosp, Tampere 33520, Finland..
    Laukkanen, Saara
    Univ Tampere, Tampere Ctr Child Hlth Res, Tampere 33520, Finland.;Tampere Univ Hosp, Tampere 33520, Finland..
    Liuksiala, Thomas
    Univ Tampere, Tampere Ctr Child Hlth Res, Tampere 33520, Finland.;Tampere Univ Hosp, Tampere 33520, Finland.;Univ Tampere, Inst Biosci & Med Technol, Tampere 33520, Finland..
    Nordlund, Jessica
    Uppsala Univ, Dept Med Sci, Mol Med & Sci Life Lab, S-75105 Uppsala, Sweden..
    Oittinen, Mikko
    Univ Tampere, Tampere Ctr Child Hlth Res, Tampere 33520, Finland.;Tampere Univ Hosp, Tampere 33520, Finland..
    Teittinen, Kaisa
    Univ Tampere, Tampere Ctr Child Hlth Res, Tampere 33520, Finland.;Tampere Univ Hosp, Tampere 33520, Finland..
    Gronroos, Toni
    Univ Tampere, Tampere Ctr Child Hlth Res, Tampere 33520, Finland.;Tampere Univ Hosp, Tampere 33520, Finland..
    St-Onge, Pascal
    Univ Montreal, CHU St Justine Res Ctr, Montreal, PQ H3T 1J4, Canada..
    Sinnett, Daniel
    Univ Montreal, CHU St Justine Res Ctr, Montreal, PQ H3T 1J4, Canada.;Univ Montreal, Fac Med, Dept Pediat, Montreal, PQ H3T 1J4, Canada..
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nykter, Matti
    Univ Tampere, Inst Biosci & Med Technol, Tampere 33520, Finland.;Tampere Univ Technol, Dept Signal Proc, Tampere 33720, Finland..
    Viiri, Keijo
    Univ Tampere, Tampere Ctr Child Hlth Res, Tampere 33520, Finland.;Tampere Univ Hosp, Tampere 33520, Finland..
    Heinaniemi, Merja
    Univ Eastern Finland, Inst Biomed, Sch Med, Kuopio 70211, Finland..
    Lohi, Olli
    Univ Tampere, Tampere Ctr Child Hlth Res, Tampere 33520, Finland.;Tampere Univ Hosp, Tampere 33520, Finland..
    Genome-wide repression of eRNA and target gene loci by the ETV6-RUNX1 fusion in acute leukemia2016In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 26, no 11, p. 1468-1477Article in journal (Refereed)
    Abstract [en]

    Approximately 20%-25% of childhood acute lymphoblastic leukemias carry the ETV6-RUNX1 (E/R) fusion gene, a fusion of two central hematopoietic transcription factors, ETV6 (TEL) and RUNX1 (AML1). Despite its prevalence, the exact genomic targets of E/R have remained elusive. We evaluated gene loci and enhancers targeted by E/R genome-wide in precursor B acute leukemia cells using global run-on sequencing (GRO-seq). We show that expression of the E/R fusion leads to widespread repression of RUNX1 motif-containing enhancers at its target gene loci. Moreover, multiple super-enhancers from the CD19(+)/CD20(+)-lineage were repressed, implicating a role in impediment of lineage commitment. In effect, the expression of several genes involved in B cell signaling and adhesion was down-regulated, and the repression depended on the wild-type DNA-binding Runt domain of RUNX1. We also identified a number of E/R-regulated annotated and de novo noncoding genes. The results provide a comprehensive genome-wide mapping between E/R-regulated key regulatory elements and genes in precursor B cell leukemia that disrupt normal B lymphopoiesis.

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  • 299. Tyden, Eva
    et al.
    Dahlberg, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlberg, Olof
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Hoglund, Johan
    Deep amplicon sequencing of preselected isolates of Parascaris equorum in beta-tubulin codons associated with benzimidazole resistance in other nematodes2014In: Parasites & Vectors, E-ISSN 1756-3305, Vol. 7, p. 410-Article in journal (Refereed)
    Abstract [en]

    Background: The development of anthelmintic resistance (AR) to macrocyclic lactones in the equine roundworm Parascaris equorum has resulted in benzimidazoles now being the most widely used substance to control Parascaris infections. However, over-reliance on one drug class is a risk factor for the development of AR. Consequently, benzimidazole resistance is widespread in several veterinary parasites, where it is associated with single nucleotide polymorphisms (SNPs) in drug targets encoded by the beta-tubulin genes. The importance of these SNPs varies between different parasitic nematodes, but it has been hypothesised that they occur, at low allele frequencies, even in unselected populations. This study investigated whether these SNPs exist in the P. equorum population and tested the hypothesis that BZ resistance can develop from pre-existing SNPs in codons 167, 198 and 200 of the beta-tubulin isotype 1 and 2 genes, reported to be associated with AR in strongylids. The efficacy of the oral paste formula fenbendazole on 11 farms in Sweden was also assessed. Methods: Two isotype-specific primer pairs were designed, one on either side of the codon 167 and one on either side of codons 198 and 200. A pool of 100 000 larvae was sequenced using deep amplicon sequencing by Illumina HiSeq. Faecal egg count reduction test was used to assess the efficacy of fenbendazole. Results: No SNPs were observed in codons 167, 198 or 200 of the beta-tubulin isotype 1 or 2 genes of P. equorum, even though 100 000 larvae were sequenced. Faecal egg count reduction testing of fenbendazole showed that this anthelmintic was still 100% effective, meaning that the likelihood of finding high allele frequency of SNPs associated with benzimidazoles resistance in P. equorum was low. Unexpectedly, the allele frequencies observed in single worms were comparable to those in pooled samples. Conclusions: We concluded that fenbendazole does not exert selection pressure on the beta-tubulin genes of isotypes 1 and 2 in P. equorum. The fact that no pre-existing SNPs were found in codons 167, 198 and 200 in P. equorum also illustrates the difficulties in generalising about AR mechanisms between different taxonomic groups of nematodes.

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  • 300.
    Täpp, Ida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Malmberg, Lovisa
    Rennel, Emma
    Majstin, Wik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Homogeneous scoring of single nucleotide polymorphisms: The 5’-nuclease ”TaqMan” assay versus Molecular beacon probes2000In: BioTechniques, ISSN 0736-6205, E-ISSN 1940-9818, Vol. 28, no 4, p. 732-738Article in journal (Refereed)
    Abstract [en]

    Homogeneous assays based on real-time fluorescence monitoring during PCR are relevant alternatives for large-scale genotyping of single-nucleotide polymorphisms (SNPs). We compared the performance of the homogeneous TaqMan 5'-nuclease assay and the Molecular Beacon assay using three SNPs in the human estrogen receptor gene as targets. When analyzing a panel of 90 DNA samples, both assays yielded a comparable power of discrimination between the genotypes of a C-to-T transition in codon 10 and a G-to-A transition in codon 594 of the estrogen receptor gene. The Molecular Beacon probes distinguished better than the TaqMan probes between homozygous and heterozygous genotypes of a C-to-G transversion in codon 325. The sensitivity of detecting one allele, present as a minority in a mixed sample, varied between the SNPs and was similar for both assays. With the Molecular Beacon assay, the measured signal ratios were proportional to the amount of the minor allele over a wider range than with the TaqMan assay at all three SNPs.

34567 251 - 300 of 323
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