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  • 101.
    Ingman, Max
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    mtDB: Human Mitochondrial Genome Database, a resource for population genetics and medical sciences2006Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 34, nr Issue Database issue, 1, s. D749-D751Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mitochondrial genome, contained in the subcellular mitochondrial network, encodes a small number of peptides pivotal for cellular energy production. Mitochondrial genes are highly polymorphic and cataloguing existing variation is of interest for medical scientists involved in the identification of mutations causing mitochondrial dysfunction, as well as for population genetics studies. Human Mitochondrial Genome Database (mtDB) (http://www.genpat.uu.se/mtDB) has provided a comprehensive database of complete human mitochondrial genomes since early 2000. At this time, owing to an increase in the number of published complete human mitochondrial genome sequences, it became necessary to provide a web-based database of human whole genome and complete coding region sequences. As of August 2005 this database contains 2104 sequences (1544 complete genome and 560 coding region) available to download or search for specific polymorphisms. Of special interest to medical researchers and population geneticists evaluating specific positions is a complete list of (currently 3311) mitochondrial polymorphisms among these sequences. Recent expansions in the capabilities of mtDB include a haplotype search function and the ability to identify and download sequences carrying particular variants.

  • 102.
    Ingman, Max
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Rate variation between mitochondrial domains and adaptive evolution in humans2007Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 16, nr 19, s. 2281-2287Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It has been proposed that as a result of human adaptation to different climates, mitochondrial genes have been affected by natural selection. To further study the selective pressure on human mitochondrial DNA, we have analysed polymorphism at the gene, domain and nucleotide site level in four geographic regions. The ratio of non-synonymous relative to synonymous substitutions is elevated for ATP6 in North Asia, ND3 in Africa and cytb in Europe relative to other mitochondrial genes. In addition, non-synonymous substitutions appear nearly five times more frequently outside core functional domains as compared with within functional domains. Therefore, a large part of the rate variation between mitochondrial genes is explained by differences in the length of the functional domain relative to the length of the gene. The accumulation of non-synonymous substitutions in the ATP6 gene among sequences from North Asia has been a gradual process over many thousands of years, consistent with relaxed purifying selection rather than recent strong selective sweeps. It is not necessary to invoke adaptive selection to explain the pattern of polymorphism in mitochondrial genes, when the most parsimonious explanation is relaxed purifying selection and the action of genetic drift.

  • 103.
    Ingman, Max
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    SNP frequency estimation using massively parallel sequencing of pooled DNA2008Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 17, nr 3, s. 383-386Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Resequencing of genomic regions that have been implicated by linkage and/or association studies to harbor genetic susceptibility loci represents a necessary step to identify causal variants. Massively parallel sequencing (MPS) offers the possibility of SNP discovery and frequency determination among pooled DNA samples. The strategies of pooling DNA samples and pooling PCR amplicons generated from individual DNA samples were evaluated, and both were found to return accurate estimates of SNP frequencies across varying levels of sequence coverage.European Journal of Human Genetics advance online publication, 15 October 2008; doi:10.1038/ejhg.2008.182.

  • 104.
    Ivansson, Emma
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gustavsson, Inger M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Genomik.
    Magnusson, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Steiner, Lori
    Magnusson, Patrik
    Erlich, Henry
    Gyllensten, Ulf B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Genomik.
    Variants of chemokine receptor 2 and interleukin 4 receptor, but not interleukin 10 or Fas ligand, increase risk of cervical cancer2007Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 121, nr 11, s. 2451-2457Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cervical cancer is caused by persistent infection of oncogenichuman papillomavirus (HPV). Most infected women clear the viruswithout developing cervical lesions and it is likely that immunologicalhost factors affect susceptibility to cervical cancer. Theimpact of the human leukocyte antigen (HLA) locus on the risk ofcervical cancer is established and several other genes involved inimmunological pathways have been suggested as biologically plausiblecandidates. The aim of this study was to examine the potentialrole of polymorphisms in 4 candidate genes by analysis of1,306 familial cervical cancer cases and 288 controls. The followinggenes and polymorphisms were studied: Chemokine receptor2 (CCR-2) V64I; Interleukin 4 receptor a (IL-4R) I75V, S503P andQ576R; Interleukin 10 (IL-10) 2592; and Fas ligand (FasL) 2844.The CCR-2 64I variant was associated with decreased risk of cervicalcancer; homozygote carriers of the 64I variant had an oddsratio of 0.31 (0.12–0.77). This association was detected in both carriersand noncarriers of the HLA DQB1*0602 cervical cancer riskallele. The IL-4R 75V variant was associated with increased riskof cervical tumors, cases homozygote for 75V had an odds ratio of1.91 (1.27–2.86) with a tendency that the association was strongerin noncarriers of the DQB1*0602 allele. We did not find any associationfor IL-10 2592, or FasL 2844, previously reported to beassociated with cervical cancer in the Dutch and Chinese populations,respectively.

  • 105.
    Ivansson, Emma L.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Juko-Pecirep, Ivana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Erlich, H. A.
    Gyllensten, Ulf B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pathway-based analysis of genetic susceptibility to cervical cancer in situ: HLA-DPB1 affects risk in Swedish women2011Inngår i: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 12, nr 8, s. 605-614Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have conducted a pathway-based analysis of genome-wide single-nucleotide polymorphism (SNP) data in order to identify genetic susceptibility factors for cervical cancer in situ. Genotypes derived from Affymetrix 500k or 5.0 arrays for 1076 cases and 1426 controls were analyzed for association, and pathways with enriched signals were identified using the SNP ratio test. The most strongly associated KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways were Asthma (empirical P=0.03), Folate biosynthesis (empirical P=0.04) and Graft-versus-host disease (empirical P=0.05). Among the 11 top-ranking pathways were 6 related to the immune response with the common denominator being genes in the major histocompatibility complex (MHC) region on chromosome 6. Further investigation of the MHC revealed a clear effect of HLA-DPB1 polymorphism on disease susceptibility. At a functional level, DPB1 alleles associated with risk and protection differ in key amino-acid residues affecting peptide-binding motifs in the extracellular domains. The results illustrate the value of pathway-based analysis to mine genome-wide data, and point to the importance of the MHC region and specifically the HLA-DPB1 locus for susceptibility to cervical cancer.

  • 106.
    Ivansson, Emma
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Magnusson, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Magnusson, Patrik
    Erlich, Henry
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    MHC loci affecting cervical cancer risk: distinguishing the effects of HLA-DQB1 and non-HLA genes TNF, LTA, TAP1 and TAP22008Inngår i: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 9, nr 7, s. 613-623Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cervical cancer has been associated with specific human leukocyte antigen (HLA) haplotypes/alleles and with polymorphisms at the nearby non-HLA loci TNF, LTA, TAP1 and TAP2. Distinguishing effects of individual loci in the major histocompatibility complex (MHC) region are difficult due to the complex linkage disequilibrium (LD) pattern characterized by high LD, punctuated by recombination hot spots. We have evaluated the association of polymorphism at HLA class II DQB1 and the TNF, LTA, TAP1 and TAP2 genes with cervical cancer risk, using 1306 familial cases and 288 controls. DQB1 was strongly associated; alleles *0301, *0402 and *0602 increased cancer susceptibility, whereas *0501 and *0603 decreased susceptibility. Among the non-HLA loci, association was only detected for the TAP2 665 polymorphism, and interallelic disequilibrium analysis indicated that this could be due to LD with DQB1. As the TAP2 665 association was seen predominantly in non-carriers of DQB1 susceptibility alleles, we hypothesized that TAP2 665 may have an effect not attributable to LD with DQB1. However, a logistic regression analysis suggested that TAP2 665 was strongly influenced by LD with DQB1. Our results emphasize the importance of large sample sizes and underscore the necessity of examining both HLA and non-HLA loci in the MHC to assign association to the correct locus.

  • 107.
    Jacobsson, Josefin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Rask-Andersen, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Moschonis, G
    Koumpitski, A
    Chrousos, G P
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Marcus, C
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Schiöth, Helgi B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Fredriksson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Genetic variants near the MGAT1 gene are associated with body weight, BMI and fatty acid metabolism among adults and children2012Inngår i: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 36, nr 1, s. 119-129Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Recently a genome-wide association analysis from five European populations identified a polymorphism located downstream of the mannosyl-(α-1,3)-glycoprotein-β-1,2-N-acetylglucosaminyltransferase (MGAT1) gene that was associated with body-weight. In the present study, associations between MGAT1 variants combined with obesity and insulin measurements were investigated in three cohorts. Levels of fatty acids and estimated measures of Δ desaturases were also investigated among adult men.

    Design: Six polymorphisms downstream of MGAT1 were genotyped in a cross-sectional cohort of 1152 Swedish men. Three polymorphisms were further analyzed in a case-control study of 1076 Swedish children and in a cross-sectional study of 2249 Greek children.

    Results: Three polymorphisms, rs12186500 (odds ratio (OR): 1.892, 95% confidence interval (CI): 1.237-2.895, P=0.003), rs1021001 (OR: 2.102, 95% CI: 1.280-3.455, P=0.003) and rs4285184 (OR: 1.587, 95% CI: 1.024-2.459, P=0.038) were associated with a higher prevalence of obesity among the adult men and a trend for obesity was observed for rs4285184 among the Swedish (OR: 1.205, 95% CI: 0.987-1.471, P=0.067) and Greek children (OR: 1.192, 95%CI: 0.978-1.454, P=0.081). Association with body weight was observed for rs12186500 (P=0.017) and rs4285184 (P=0.024) among the men. The rs1021001 and rs4285184 were also associated with body mass index (BMI) in the two Swedish cohorts and similar trends were observed among the Greek children. The combined effect size for rs1021001 and rs4285184 on BMI z-score from a meta-analysis was 0.233 (95% CI:0.093-0.373, P=0.001) and 0.147 (95% CI:0.057-0.236, P=0.001), respectively. We further observed associations between the genetic variants and fatty acids (P<0.039) and estimated measures of Δ desaturases (P<0.040), as well as interactions for rs12186500 (P<0.019) with an effect on BMI. No association was found with homeostatic model assessment-insulin resistance in any cohort but increased insulin levels, insulin response and decreased insulin sensitivity were observed among the children (P<0.038).

    Conclusion: Genetic variants downstream MGAT1 seem to influence susceptibility to obesity. Moreover, these genetic variants affect the levels of serum unsaturated fatty acids and Δ desaturase indices, variables previously shown to correlate with obesity.

  • 108.
    Jiang, Jiyang
    et al.
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia.
    Thalamuthu, Anbupalam
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia.
    Ho, Jennifer E.
    Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA;Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA.
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
    Ek, Weronica E
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Brown, David A.
    St Vincents Hosp, St Vincents Ctr Appl Med Res, Darlinghurst, NSW, Australia;Westmead Inst Med Res, Inst Clin Pathol & Med Res, Westmead, NSW, Australia;Westmead Hosp, Westmead, NSW, Australia.
    Breit, Samuel N.
    St Vincents Hosp, St Vincents Ctr Appl Med Res, Darlinghurst, NSW, Australia.
    Wang, Thomas J.
    Vanderbilt Univ, Dept Med, Div Cardiol, Nashville, TN USA.
    Gyllensten, Ulf B.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Chen, Ming-Huei
    NHLBI, Populat Sci Branch, NIH, Framingham, MA USA;Framingham Heart Dis Epidemiol Study, Framingham, MA USA.
    Enroth, Stefan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Januzzi, James L., Jr.
    Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Armstrong, Nicola J.
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia;Murdoch Univ, Math & Stat, Perth, WA, Australia.
    Kwok, John B.
    Neurosci Res Australia, Randwick, NSW, Australia;Univ New South Wales, Sch Med Sci, Sydney, NSW, Australia.
    Schofield, Peter R.
    Neurosci Res Australia, Randwick, NSW, Australia;Univ New South Wales, Sch Med Sci, Sydney, NSW, Australia.
    Wen, Wei
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia;Prince Wales Hosp, Neuropsychiat Inst, Randwick, NSW, Australia.
    Trollor, Julian N.
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia;Univ New South Wales, Sch Psychiat, Dept Dev Disabil Neuropsychiat, Sydney, NSW, Australia.
    Johansson, Åsa
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England.
    Vasan, Ramachandran S.
    Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Boston, MA 02118 USA;Boston Univ, Sch Med, Dept Med, Epidemiol Sect, Boston, MA 02118 USA;Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA;Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA;Natl Heart Lung & Blood Inst, Boston, MA USA;Boston Univ, Framingham Heart Study, Boston, MA 02215 USA.
    Sachdev, Perminder S.
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia;Prince Wales Hosp, Neuropsychiat Inst, Randwick, NSW, Australia.
    Mather, Karen A.
    Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia.
    A Meta-Analysis of Genome-Wide Association Studies of Growth Differentiation Factor-15 Concentration in Blood2018Inngår i: Frontiers in Genetics, ISSN 1664-8021, E-ISSN 1664-8021, Vol. 9, artikkel-id 97Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Blood levels of growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1 (MIC-1), have been associated with various pathological processes and diseases, including cardiovascular disease and cancer. Prior studies suggest genetic factors play a role in regulating blood MIC-1/GDF-15 concentration. In the current study, we conducted the largest genome-wide association study (GWAS) to date using a sample of similar to 5,400 community-based Caucasian participants, to determine the genetic variants associated with MIC-1/GDF-15 blood concentration. Conditional and joint (COJO), gene-based association, and gene-set enrichment analyses were also carried out to identify novel loci, genes, and pathways. Consistent with prior results, a locus on chromosome 19, which includes nine single nucleotide polymorphisms (SNPs) (top SNP, rs888663, p = 1.690 x 10(-35)), was significantly associated with blood MIC-1/GDF-15 concentration, and explained 21.47% of its variance. COJO analysis showed evidence for two independent signals within this locus. Gene-based analysis confirmed the chromosome 19 locus association and in addition, a putative locus on chromosome 1. Gene-set enrichment analyses showed that the "COPI-mediated anterograde transport" gene-set was associated with MIC-1/GDF15 blood concentration with marginal significance after FDR correction (p = 0.067). In conclusion, a locus on chromosome 19 was associated with MIC-1/GDF-15 blood concentration with genome-wide significance, with evidence for a new locus (chromosome 1). Future studies using independent cohorts are needed to confirm the observed associations especially for the chromosomes 1 locus, and to further investigate and identify the causal SNPs that contribute to MIC-1/GDF-15 levels.

  • 109.
    Johanneson, Bo
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Chen, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Enroth, Stefan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Cui, Tao
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gyllensten, Ulf
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Systematic validation of hypothesis-driven candidate genes for cervical cancer in a genome-wide association study2014Inngår i: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 35, nr 9, s. 2084-2088Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A large number of genetic associations with cervical cancer have been reported in hypothesis-driven candidate gene studies, but most studies have not included an independent replication or the results have been inconsistent between studies. In order to independently validate these associations, we re-examined 58 candidate gene/regions previously reported to be associated with cervical cancer using the gene-based Adaptive Rank Truncated Product (ARTP) test in a genome-wide association study of 1,034 cervical cancer patients and 3,948 controls from the Swedish population. Of the 58 gene/regions, 8 had a nominal p-value < 0.05 (Tumor necrosis factor [TNF], p = 5.0×10(-4); DEAD (Asp-Glu-Ala-Asp) box helicase 1 [DDX1], p = 2.2×10(-3); Exonuclease 1 [EXO1], p=4.7×10(-3); Excision repair cross-complementing rodent repair deficiency, complementation group 1 [ERCC1], p = 0.020; Transmembrane channel-like 6 and 8 genes [TMC6-TMC8], p = 0.023; Secreted phosphoprotein 1 [SPP1], p= 0.028; v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 [ERBB2], p = 0.033 and Chloride channel, voltage-sensitive 7 [CLCN7], p = 0.047). After correction for multiple testing only TNF remained statistically significant (p = 0.028). Two single-nucleotide polymorphisms that are in nearly perfect linkage disequilibrium (LD) (rs2857602 and rs2844484) contributed most to the association with TNF. However, they are not independent from the previously reported associations within the MHC region. The very low number of previously reported associations with cervical cancer that replicate in the Swedish population underscore the need to apply more stringent criteria when reporting associations, including the prerequisite of replicating the association as part of the original study.

  • 110.
    Johansson, Asa
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Vavruch-Nilsson, Veronika
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Edin-Liljegren, Anette
    Sjölander, Per
    Gyllensten, Ulf
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Linkage disequilibrium between microsatellite markers in the Swedish Sami relative to a worldwide selection of populations.2005Inngår i: Hum Genet, ISSN 0340-6717, Vol. 116, nr 1-2, s. 105-13Artikkel i tidsskrift (Fagfellevurdert)
  • 111.
    Johansson, Åsa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Continuous Aging of the Human DNA Methylome Throughout the Human Lifespan2013Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 6, s. e67378-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    DNA methylation plays an important role in development of disease and the process of aging. In this study we examine DNA methylation at 476,366 sites throughout the genome of white blood cells from a population cohort (N = 421) ranging in age from 14 to 94 years old. Age affects DNA methylation at almost one third (29%) of the sites (Bonferroni adjusted P-value <0.05), of which 60.5% becomes hypomethylated and 39.5% hypermethylated with increasing age. DNA methylation sites that are located within CpG islands (CGIs) more often become hypermethylated compared to sites outside an island. CpG sites in promoters are more unaffected by age, whereas sites in enhancers more often becomes hypo- or hypermethylated. Hypermethylated sites are overrepresented among genes that are involved in DNA binding, transcription regulation, processes of anatomical structure and developmental process and cortex neuron differentiation (P-value down to P = 9.14*10−67). By contrast, hypomethylated sites are not strongly overrepresented among any biological function or process. Our results indicate that the 23% of the variation in DNA methylation is attributed chronological age, and that hypermethylation is more site-specific than hypomethylation. It appears that the change in DNA methylation partly overlap with regions that change histone modifications with age, indicating an interaction between the two major epigenetic mechanisms. Epigenetic modifications and change in gene expression over time most likely reflects the natural process of aging and variation between individuals might contribute to the development of age-related phenotypes and diseases such as type II diabetes, autoimmune and cardiovascular disease.

  • 112.
    Johansson, Åsa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Palmblad, Magnus
    Deelder, Andre M.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Identification of genetic variants influencing the human plasma proteome2013Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, nr 12, s. 4673-4678Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genetic variants influencing the transcriptome have been extensively studied. However, the impact of the genetic factors on the human proteome is largely unexplored, mainly due to lack of suitable high-throughput methods. Here we present unique and comprehensive identification of genetic variants affecting the human plasma protein profile by combining high-throughput and high-resolution mass spectrometry (MS) with genome-wide SNP data. We identified and quantified the abundance of 1,056 tryptic-digested peptides, representing 163 proteins in the plasma of 1,060 individuals from two population-based cohorts. The abundance level of almost one-fifth (19%) of the peptides was found to be heritable, with heritability ranging from 0.08 to 0.43. The levels of 60 peptides from 25 proteins, 15% of the proteins studied, were influenced by cis-acting SNPs. We identified and replicated individual cis-acting SNPs (combined P value ranging from 3.1 x 10(-52) to 2.9 x 10(-12)) influencing 11 peptides from 5 individual proteins. These SNPs represent both regulatory SNPs and nonsynonymous changes defining well-studied disease alleles such as the epsilon 4 allele of apolipoprotein E (APOE), which has been shown to increase risk of Alzheimer's disease. Our results show that high-throughput mass spectrometry represents a promising method for large-scale characterization of the human proteome, allowing for both quantification and sequencing of individual proteins. Abundance and peptide composition of a protein plays an important role in the etiology, diagnosis, and treatment of a number of diseases. A better understanding of the genetic impact on the plasma proteome is therefore important for evaluating potential biomarkers and therapeutic agents for common diseases.

  • 113.
    Johansson, Åsa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Ingman, Max
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Mack, Steven J
    Erlich, Henry
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Genetic origin of the Swedish Sami inferred from HLA class I and class II allele frequencies2008Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 16, nr 11, s. 1341-1349Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sami of northern Scandinavia are genetic outliers among European populations and their origin has been difficult to determine. In order to study the genetic origin of the Swedish Sami, we have performed high-resolution typing of the class I HLA-A and -B loci and the class II DRB1, DQB1 and DQA1 loci in the northern and southern Swedish Sami. Several of the common class I alleles in Sami (B*0702, B*1501, B*4002 and A*0301) are found at high frequency in other European populations. However, a number of class I and class II alleles (B*4001, A*2402, DRB1*0901 and DRB1*1101) in the Swedish Sami are characteristic of Asian populations. Admixture analyses indicate that 87% of the Sami gene pool is of European origin and that the Asian contribution is 13%. Our HLA analyses indicate a higher proportion of Asian ancestry in the Sami than shown by previous genetic studies.

  • 114.
    Johansson, Åsa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Jonasson, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Extended haplotypes in the growth hormone releasing hormone receptor gene (GHRHR) are associated with normal variation in height2009Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, nr 2, s. e4464-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mutations in the gene for growth hormone releasing hormone receptor (GHRHR) cause isolated growth hormone deficiency (IGHD) but this gene has not been found to affect normal variation in height. We performed a whole genome linkage analysis for height in a population from northern Sweden and identified a region on chromosome 7 with a lod-score of 4.7. The GHRHR gene is located in this region and typing of tagSNPs identified a haplotype that is associated with height (p = 0.00077) in the original study population. Analysis of a sample from an independent population from the most northern part of Sweden also showed an association with height (p = 0.0039) but with another haplotype in the GHRHR gene. Both haplotypes span the 3' part of the GHRHR gene, including the region in which most of the mutations in IGHD have been located. The effect size of these haplotypes are larger than that of any gene previously associated with height, which indicates that GHRHR might be one of the most important genes so far identified affecting normal variation in human height.

  • 115.
    Johansson, Åsa
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Karlsson, P
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    A novel method for automatic genotyping of microsatellite markers based on parametric pattern recognition.2003Inngår i: Hum Genet, Vol. 113, s. 316-Artikkel i tidsskrift (Fagfellevurdert)
  • 116.
    Johansson, Åsa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Marroni, Fabio
    Hayward, Caroline
    Franklin, Christopher S.
    Kirichenko, Anatoly V.
    Jonasson, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Hicks, Andrew A.
    Vitart, Veronique
    Isaacs, Aaron
    Axenovich, Tatiana
    Campbell, Susan
    Dunlop, Malcolm G.
    Floyd, Jamie
    Hastie, Nick
    Hofman, Albert
    Knott, Sara
    Kolcic, Ivana
    Pichler, Irene
    Polasek, Ozren
    Rivadeneira, Fernando
    Tenesa, Albert
    Uitterlinden, André G.
    Wild, Sarah H.
    Zorkoltseva, Irina V.
    Meitinger, Thomas
    Wilson, James F.
    Rudan, Igor
    Campbell, Harry
    Pattaro, Cristian
    Pramstaller, Peter
    Oostra, Ben A.
    Wright, Alan F.
    Duijn, Cornelia M. van
    Aulchenko, Yurii S.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Common variants in the JAZF1 gene associated with height identified by linkage and genome-wide association analysis2009Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 18, nr 2, s. 373-380Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genes for height has gained interest for decades, but only recently have candidate genes started to be identified. We have performed linkage analysis and genome-wide association for height in approximately 4,000 individuals from five European populations. A total of 5 chromosomal regions showed suggestive linkage and in one of these regions, two SNPs (rs849140 and rs1635852) were associated with height (nominal p=7.0 x 10(-8) and p=9.6 x 10(-7) respectively). In total, five SNPs across the genome showed an association with height that reached the threshold of genome-wide significance (nominal p<1.6 x 10(-7)). The association with height was replicated for two SNPs (rs1635852 and rs849140) using three independent studies (N=31,077, N=1,268 and N=5,746) with overall meta p-values of 9.4x10(-10) and 5.3x10(-8). These SNPs are located in the JAZF1 gene, which has recently been associated with type II diabetes, prostate and endometrial cancer. JAZF1 is a transcriptional repressor of NR2C2, which results in low IGF1 serum concentrations, perinatal and early postnatal hypoglycaemia and growth retardation when knocked-out in mice. Both the linkage and association analyses independently identified the JAZF1 region affecting human height. We have demonstrated, through replication in additional independent populations, the consistency of the effect of the JAZF1 SNPs on height. Since this gene also has a key function in the metabolism of growth, JAZF1 represents one of the strongest candidates influencing human height so far identified.

  • 117.
    Johansson, Åsa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Marroni, Fabio
    Hayward, Caroline
    Franklin, Christopher S.
    Kirichenko, Anatoly V.
    Jonasson, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Hicks, Andrew A.
    Vitart, Veronique
    Isaacs, Aaron
    Axenovich, Tatiana
    Campbell, Susan
    Floyd, Jamie
    Hastie, Nick
    Knott, Sara
    Lauc, Gordan
    Pichler, Irene
    Rotim, Kresimir
    Wild, Sarah H.
    Zorkoltseva, Irina V.
    Wilson, James F.
    Rudan, Igor
    Campbell, Harry
    Pattaro, Cristian
    Pramstaller, Peter
    Oostra, Ben A.
    Wright, Alan F.
    van Duijn, Cornelia M.
    Aulchenko, Yurii S.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Linkage and genome-wide association analysis of obesity-related phenotypes: association of weight with the MGAT1 gene2010Inngår i: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 18, nr 4, s. 803-808Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    As major risk-factors for diabetes and cardiovascular diseases, the genetic contribution to obesity-related traits has been of interest for decades. Recently, a limited number of common genetic variants, which have replicated in different populations, have been identified. One approach to increase the statistical power in genetic mapping studies is to focus on populations with increased levels of linkage disequilibrium (LD) and reduced genetic diversity. We have performed joint linkage and genome-wide association analyses for weight and BMI in 3,448 (linkage) and 3,925 (association) partly overlapping healthy individuals from five European populations. A total of four chromosomal regions (two for weight and two for BMI) showed suggestive linkage (lod >2.69) either in one of the populations or in the joint data. At the genome-wide level (nominal P < 1.6 × 10−7, Bonferroni-adjusted P < 0.05) one single-nucleotide polymorphism (SNP) (rs12517906) (nominal P = 7.3 × 10−8) was associated with weight, whereas none with BMI. The SNP associated with weight is located close to MGAT1. The monoacylglycerol acyltransferase (MGAT) enzyme family is known to be involved in dietary fat absorption. There was no overlap between the linkage regions and the associated SNPs. Our results show that genetic effects influencing weight and BMI are shared across diverse European populations, even though some of these populations have experienced recent population bottlenecks and/or been affected by genetic drift. The analysis enabled us to identify a new candidate gene, MGAT1, associated with weight in women.

  • 118. Joshi, Peter K
    et al.
    Esko, Tonu
    Mattsson, Hannele
    Eklund, Niina
    Gandin, Ilaria
    Nutile, Teresa
    Jackson, Anne U
    Schurmann, Claudia
    Smith, Albert V
    Zhang, Weihua
    Okada, Yukinori
    Stančáková, Alena
    Faul, Jessica D
    Zhao, Wei
    Bartz, Traci M
    Concas, Maria Pina
    Franceschini, Nora
    Enroth, Stefan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Vitart, Veronique
    Trompet, Stella
    Guo, Xiuqing
    Chasman, Daniel I
    O'Connel, Jeffrey R
    Corre, Tanguy
    Nongmaithem, Suraj S
    Chen, Yuning
    Mangino, Massimo
    Ruggiero, Daniela
    Traglia, Michela
    Farmaki, Aliki-Eleni
    Kacprowski, Tim
    Bjonnes, Andrew
    van der Spek, Ashley
    Wu, Ying
    Giri, Anil K
    Yanek, Lisa R
    Wang, Lihua
    Hofer, Edith
    Rietveld, Cornelius A
    McLeod, Olga
    Cornelis, Marilyn C
    Pattaro, Cristian
    Verweij, Niek
    Baumbach, Clemens
    Abdellaoui, Abdel
    Warren, Helen R
    Vuckovic, Dragana
    Mei, Hao
    Bouchard, Claude
    Perry, John R B
    Cappellani, Stefania
    Mirza, Saira S
    Benton, Miles C
    Broeckel, Ulrich
    Medland, Sarah E
    Lind, Penelope A
    Malerba, Giovanni
    Drong, Alexander
    Yengo, Loic
    Bielak, Lawrence F
    Zhi, Degui
    van der Most, Peter J
    Shriner, Daniel
    Mägi, Reedik
    Hemani, Gibran
    Karaderi, Tugce
    Wang, Zhaoming
    Liu, Tian
    Demuth, Ilja
    Zhao, Jing Hua
    Meng, Weihua
    Lataniotis, Lazaros
    van der Laan, Sander W
    Bradfield, Jonathan P
    Wood, Andrew R
    Bonnefond, Amelie
    Ahluwalia, Tarunveer S
    Hall, Leanne M
    Salvi, Erika
    Yazar, Seyhan
    Carstensen, Lisbeth
    de Haan, Hugoline G
    Abney, Mark
    Afzal, Uzma
    Allison, Matthew A
    Amin, Najaf
    Asselbergs, Folkert W
    Bakker, Stephan J L
    Barr, R Graham
    Baumeister, Sebastian E
    Benjamin, Daniel J
    Bergmann, Sven
    Boerwinkle, Eric
    Bottinger, Erwin P
    Campbell, Archie
    Chakravarti, Aravinda
    Chan, Yingleong
    Chanock, Stephen J
    Chen, Constance
    Chen, Y-D Ida
    Collins, Francis S
    Connell, John
    Correa, Adolfo
    Cupples, L Adrienne
    Smith, George Davey
    Davies, Gail
    Dörr, Marcus
    Ehret, Georg
    Ellis, Stephen B
    Feenstra, Bjarke
    Feitosa, Mary F
    Ford, Ian
    Fox, Caroline S
    Frayling, Timothy M
    Friedrich, Nele
    Geller, Frank
    Scotland, Generation
    Gillham-Nasenya, Irina
    Gottesman, Omri
    Graff, Misa
    Grodstein, Francine
    Gu, Charles
    Haley, Chris
    Hammond, Christopher J
    Harris, Sarah E
    Harris, Tamara B
    Hastie, Nicholas D
    Heard-Costa, Nancy L
    Heikkilä, Kauko
    Hocking, Lynne J
    Homuth, Georg
    Hottenga, Jouke-Jan
    Huang, Jinyan
    Huffman, Jennifer E
    Hysi, Pirro G
    Ikram, M Arfan
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Joensuu, Anni
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jousilahti, Pekka
    Jukema, J Wouter
    Kähönen, Mika
    Kamatani, Yoichiro
    Kanoni, Stavroula
    Kerr, Shona M
    Khan, Nazir M
    Koellinger, Philipp
    Koistinen, Heikki A
    Kooner, Manraj K
    Kubo, Michiaki
    Kuusisto, Johanna
    Lahti, Jari
    Launer, Lenore J
    Lea, Rodney A
    Lehne, Benjamin
    Lehtimäki, Terho
    Liewald, David C M
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Loh, Marie
    Lokki, Marja-Liisa
    London, Stephanie J
    Loomis, Stephanie J
    Loukola, Anu
    Lu, Yingchang
    Lumley, Thomas
    Lundqvist, Annamari
    Männistö, Satu
    Marques-Vidal, Pedro
    Masciullo, Corrado
    Matchan, Angela
    Mathias, Rasika A
    Matsuda, Koichi
    Meigs, James B
    Meisinger, Christa
    Meitinger, Thomas
    Menni, Cristina
    Mentch, Frank D
    Mihailov, Evelin
    Milani, Lili
    Montasser, May E
    Montgomery, Grant W
    Morrison, Alanna
    Myers, Richard H
    Nadukuru, Rajiv
    Navarro, Pau
    Nelis, Mari
    Nieminen, Markku S
    Nolte, Ilja M
    O'Connor, George T
    Ogunniyi, Adesola
    Padmanabhan, Sandosh
    Palmas, Walter R
    Pankow, James S
    Patarcic, Inga
    Pavani, Francesca
    Peyser, Patricia A
    Pietilainen, Kirsi
    Poulter, Neil
    Prokopenko, Inga
    Ralhan, Sarju
    Redmond, Paul
    Rich, Stephen S
    Rissanen, Harri
    Robino, Antonietta
    Rose, Lynda M
    Rose, Richard
    Sala, Cinzia
    Salako, Babatunde
    Salomaa, Veikko
    Sarin, Antti-Pekka
    Saxena, Richa
    Schmidt, Helena
    Scott, Laura J
    Scott, William R
    Sennblad, Bengt
    Seshadri, Sudha
    Sever, Peter
    Shrestha, Smeeta
    Smith, Blair H
    Smith, Jennifer A
    Soranzo, Nicole
    Sotoodehnia, Nona
    Southam, Lorraine
    Stanton, Alice V
    Stathopoulou, Maria G
    Strauch, Konstantin
    Strawbridge, Rona J
    Suderman, Matthew J
    Tandon, Nikhil
    Tang, Sian-Tsun
    Taylor, Kent D
    Tayo, Bamidele O
    Töglhofer, Anna Maria
    Tomaszewski, Maciej
    Tšernikova, Natalia
    Tuomilehto, Jaakko
    Uitterlinden, Andre G
    Vaidya, Dhananjay
    van Hylckama Vlieg, Astrid
    van Setten, Jessica
    Vasankari, Tuula
    Vedantam, Sailaja
    Vlachopoulou, Efthymia
    Vozzi, Diego
    Vuoksimaa, Eero
    Waldenberger, Melanie
    Ware, Erin B
    Wentworth-Shields, William
    Whitfield, John B
    Wild, Sarah
    Willemsen, Gonneke
    Yajnik, Chittaranjan S
    Yao, Jie
    Zaza, Gianluigi
    Zhu, Xiaofeng
    Salem, Rany M
    Melbye, Mads
    Bisgaard, Hans
    Samani, Nilesh J
    Cusi, Daniele
    Mackey, David A
    Cooper, Richard S
    Froguel, Philippe
    Pasterkamp, Gerard
    Grant, Struan F A
    Hakonarson, Hakon
    Ferrucci, Luigi
    Scott, Robert A
    Morris, Andrew D
    Palmer, Colin N A
    Dedoussis, George
    Deloukas, Panos
    Bertram, Lars
    Lindenberger, Ulman
    Berndt, Sonja I
    Lindgren, Cecilia M
    Timpson, Nicholas J
    Tönjes, Anke
    Munroe, Patricia B
    Sørensen, Thorkild I A
    Rotimi, Charles N
    Arnett, Donna K
    Oldehinkel, Albertine J
    Kardia, Sharon L R
    Balkau, Beverley
    Gambaro, Giovanni
    Morris, Andrew P
    Eriksson, Johan G
    Wright, Margie J
    Martin, Nicholas G
    Hunt, Steven C
    Starr, John M
    Deary, Ian J
    Griffiths, Lyn R
    Tiemeier, Henning
    Pirastu, Nicola
    Kaprio, Jaakko
    Wareham, Nicholas J
    Pérusse, Louis
    Wilson, James G
    Girotto, Giorgia
    Caulfield, Mark J
    Raitakari, Olli
    Boomsma, Dorret I
    Gieger, Christian
    van der Harst, Pim
    Hicks, Andrew A
    Kraft, Peter
    Sinisalo, Juha
    Knekt, Paul
    Johannesson, Magnus
    Magnusson, Patrik K E
    Hamsten, Anders
    Schmidt, Reinhold
    Borecki, Ingrid B
    Vartiainen, Erkki
    Becker, Diane M
    Bharadwaj, Dwaipayan
    Mohlke, Karen L
    Boehnke, Michael
    van Duijn, Cornelia M
    Sanghera, Dharambir K
    Teumer, Alexander
    Zeggini, Eleftheria
    Metspalu, Andres
    Gasparini, Paolo
    Ulivi, Sheila
    Ober, Carole
    Toniolo, Daniela
    Rudan, Igor
    Porteous, David J
    Ciullo, Marina
    Spector, Tim D
    Hayward, Caroline
    Dupuis, Josée
    Loos, Ruth J F
    Wright, Alan F
    Chandak, Giriraj R
    Vollenweider, Peter
    Shuldiner, Alan R
    Ridker, Paul M
    Rotter, Jerome I
    Sattar, Naveed
    Gyllensten, Ulf
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    North, Kari E
    Pirastu, Mario
    Psaty, Bruce M
    Weir, David R
    Laakso, Markku
    Gudnason, Vilmundur
    Takahashi, Atsushi
    Chambers, John C
    Kooner, Jaspal S
    Strachan, David P
    Campbell, Harry
    Hirschhorn, Joel N
    Perola, Markus
    Polašek, Ozren
    Wilson, James F
    Directional dominance on stature and cognition in diverse human populations2015Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 523, nr 7561, s. 459-462Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

  • 119. Kaiser, Vera B
    et al.
    Svinti, Victoria
    Prendergast, James G
    Chau, You-Ying
    Campbell, Archie
    Patarcic, Inga
    Barroso, Inês
    Joshi, Peter K
    Hastie, Nicholas D
    Miljkovic, Ana
    Taylor, Martin S
    Scotland, Generation
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Memari, Yasin
    Kolb-Kokocinski, Anja
    Wright, Alan F
    Gyllensten, Ulf
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Durbin, Richard
    Rudan, Igor
    Campbell, Harry
    Polašek, Ozren
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sauer, Sascha
    Porteous, David J
    Fraser, Ross M
    Drake, Camilla
    Vitart, Veronique
    Hayward, Caroline
    Semple, Colin A
    Wilson, James F
    Homozygous loss-of-function variants in European cosmopolitan and isolate populations2015Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, nr 19, s. 5464-5475Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Homozygous Loss of Function (HLOF) variants provide a valuable window on gene function in humans, as well as an inventory of the human genes that are not essential for survival and reproduction. All humans carry at least a few HLOF variants, but the exact number of inactivated genes that can be tolerated is currently unknown - as are the phenotypic effects of losing function for most human genes. Here, we make use of 1,432 whole exome sequences from five European populations to expand the catalogue of known human HLOF mutations; after stringent filtering of variants in our dataset, we identify a total of 173 HLOF mutations, 76 (44%) of which have not been observed previously. We find that population isolates are particularly well suited to surveys of novel HLOF genes because individuals in such populations carry extensive runs of homozygosity, which we show are enriched for novel, rare HLOF variants. Further, we make use of extensive phenotypic data to show that most HLOFs, ascertained in population-based samples, appear to have little detectable effect on the phenotype. On the contrary, we document several genes directly implicated in disease that seem to tolerate HLOF variants. Overall HLOF genes are enriched for olfactory receptor function and are expressed in testes more often than expected, consistent with reduced purifying selection and incipient pseudogenisation.

  • 120. Klug, Stefanie J
    et al.
    Ressing, Meike
    Koenig, Jochem
    Abba, Martin C
    Agorastos, Theodoros
    Brenna, Sylvia M F
    Ciotti, Marco
    Das, B R
    Del Mistro, Annarosa
    Dybikowska, Aleksandra
    Giuliano, Anna R
    Gudleviciene, Zivile
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Haws, Andrea L F
    Helland, Aslaug
    Herrington, C Simon
    Hildesheim, Alan
    Humbey, Olivier
    Jee, Sun H
    Kim, Jae Weon
    Madeleine, Margaret M
    Menczer, Joseph
    Ngan, Hextan Y S
    Nishikawa, Akira
    Niwa, Yoshimitsu
    Pegoraro, Rosemary
    Pillai, M R
    Ranzani, Gulielmina
    Rezza, Giovanni
    Rosenthal, Adam N
    Roychoudhury, Susanta
    Saranath, Dhananjaya
    Schmitt, Virginia M
    Sengupta, Sharmila
    Settheetham-Ishida, Wannapa
    Shirasawa, Hiroshi
    Snijders, Peter J F
    Stoler, Mark H
    Suárez-Rincón, Angel E
    Szarka, Krisztina
    Tachezy, Ruth
    Ueda, Masatsugu
    van der Zee, Ate G J
    von Knebel Doeberitz, Magnus
    Wu, Ming-Tsang
    Yamashita, Tsuyoshi
    Zehbe, Ingeborg
    Blettner, Maria
    TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies2009Inngår i: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 10, nr 8, s. 772-784Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Cervical cancer is caused primarily by human papillomaviruses (HPV). The polymorphism rs1042522 at codon 72 of the TP53 tumour-suppressor gene has been investigated as a genetic cofactor. More than 80 studies were done between 1998 and 2006, after it was initially reported that women who are homozygous for the arginine allele had a risk for cervical cancer seven times higher than women who were heterozygous for the allele. However, results have been inconsistent. Here we analyse pooled data from 49 studies to determine whether there is an association between TP53 codon 72 polymorphism and cervical cancer. METHODS: Individual data on 7946 cases and 7888 controls from 49 different studies worldwide were reanalysed. Odds ratios (OR) were estimated using logistic regression, stratifying by study and ethnic origin. Subgroup analyses were done for infection with HPV, ethnic origin, Hardy-Weinberg equilibrium, study quality, and the material used to determine TP53 genotype. FINDINGS: The pooled estimates (OR) for invasive cervical cancer were 1.22 (95% CI 1.08-1.39) for arginine homozygotes compared with heterozygotes, and 1.13 (0.94-1.35) for arginine homozygotes versus proline homozygotes. Subgroup analyses showed significant excess risks only in studies where controls were not in Hardy-Weinberg equilibrium (1.71 [1.21-2.42] for arginine homozygotes compared with heterozygotes), in non-epidemiological studies (1.35 [1.15-1.58] for arginine homozygotes compared with heterozygotes), and in studies where TP53 genotype was determined from tumour tissue (1.39 [1.13-1.73] for arginine homozygotes compared with heterozygotes). Null results were noted in studies with sound epidemiological design and conduct (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes), and studies in which TP53 genotype was determined from white blood cells (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes). INTERPRETATION: Subgroup analyses indicated that excess risks were most likely not due to clinical or biological factors, but to errors in study methods. No association was found between cervical cancer and TP53 codon 72 polymorphism when the analysis was restricted to methodologically sound studies.

  • 121. Koettgen, Anna
    et al.
    Albrecht, Eva
    Teumer, Alexander
    Vitart, Veronique
    Krumsiek, Jan
    Hundertmark, Claudia
    Pistis, Giorgio
    Ruggiero, Daniela
    O'Seaghdha, Conall M.
    Haller, Toomas
    Yang, Qiong
    Tanaka, Toshiko
    Johnson, Andrew D.
    Kutalik, Zoltan
    Smith, Albert V.
    Shi, Julia
    Struchalin, Maksim
    Middelberg, Rita P. S.
    Brown, Morris J.
    Gaffo, Angelo L.
    Pirastu, Nicola
    Li, Guo
    Hayward, Caroline
    Zemunik, Tatijana
    Huffman, Jennifer
    Yengo, Loic
    Zhao, Jing Hua
    Demirkan, Ayse
    Feitosa, Mary F.
    Liu, Xuan
    Malerba, Giovanni
    Lopez, Lorna M.
    van der Harst, Pim
    Li, Xinzhong
    Kleber, Marcus E.
    Hicks, Andrew A.
    Nolte, Ilja M.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Murgia, Federico
    Wild, Sarah H.
    Bakker, Stephan J. L.
    Peden, John F.
    Dehghan, Abbas
    Steri, Maristella
    Tenesa, Albert
    Lagou, Vasiliki
    Salo, Perttu
    Mangino, Massimo
    Rose, Lynda M.
    Lehtimaki, Terho
    Woodward, Owen M.
    Okada, Yukinori
    Tin, Adrienne
    Mueller, Christian
    Oldmeadow, Christopher
    Putku, Margus
    Czamara, Darina
    Kraft, Peter
    Frogheri, Laura
    Thun, Gian Andri
    Grotevendt, Anne
    Gislason, Gauti Kjartan
    Harris, Tamara B.
    Launer, Lenore J.
    McArdle, Patrick
    Shuldiner, Alan R.
    Boerwinkle, Eric
    Coresh, Josef
    Schmidt, Helena
    Schallert, Michael
    Martin, Nicholas G.
    Montgomery, Grant W.
    Kubo, Michiaki
    Nakamura, Yusuke
    Tanaka, Toshihiro
    Munroe, Patricia B.
    Samani, Nilesh J.
    Jacobs, David R., Jr.
    Liu, Kiang
    D'Adamo, Pio
    Ulivi, Sheila
    Rotter, Jerome I.
    Psaty, Bruce M.
    Vollenweider, Peter
    Waeber, Gerard
    Campbell, Susan
    Devuyst, Olivier
    Navarro, Pau
    Kolcic, Ivana
    Hastie, Nicholas
    Balkau, Beverley
    Froguel, Philippe
    Esko, Tonu
    Salumets, Andres
    Khaw, Kay Tee
    Langenberg, Claudia
    Wareham, Nicholas J.
    Isaacs, Aaron
    Kraja, Aldi
    Zhang, Qunyuan
    Wild, Philipp S.
    Scott, Rodney J.
    Holliday, Elizabeth G.
    Org, Elin
    Viigimaa, Margus
    Bandinelli, Stefania
    Metter, Jeffrey E.
    Lupo, Antonio
    Trabetti, Elisabetta
    Sorice, Rossella
    Doering, Angela
    Lattka, Eva
    Strauch, Konstantin
    Theis, Fabian
    Waldenberger, Melanie
    Wichmann, H-Erich
    Davies, Gail
    Gow, Alan J.
    Bruinenberg, Marcel
    Stolk, Ronald P.
    Kooner, Jaspal S.
    Zhang, Weihua
    Winkelmann, Bernhard R.
    Boehm, Bernhard O.
    Lucae, Susanne
    Penninx, Brenda W.
    Smit, Johannes H.
    Curhan, Gary
    Mudgal, Poorva
    Plenge, Robert M.
    Portas, Laura
    Persico, Ivana
    Kirin, Mirna
    Wilson, James F.
    Leach, Irene Mateo
    van Gilst, Wiek H.
    Goel, Anuj
    Ongen, Halit
    Hofman, Albert
    Rivadeneira, Fernando
    Uitterlinden, Andre G.
    Imboden, Medea
    von Eckardstein, Arnold
    Cucca, Francesco
    Nagaraja, Ramaiah
    Piras, Maria Grazia
    Nauck, Matthias
    Schurmann, Claudia
    Budde, Kathrin
    Ernst, Florian
    Farrington, Susan M.
    Theodoratou, Evropi
    Prokopenko, Inga
    Stumvoll, Michael
    Jula, Antti
    Perola, Markus
    Salomaa, Veikko
    Shin, So-Youn
    Spector, Tim D.
    Sala, Cinzia
    Ridker, Paul M.
    Kaehoenen, Mika
    Viikari, Jorma
    Hengstenberg, Christian
    Nelson, Christopher P.
    Meschia, James F.
    Nalls, Michael A.
    Sharma, Pankaj
    Singleton, Andrew B.
    Kamatani, Naoyuki
    Zeller, Tanja
    Burnier, Michel
    Attia, John
    Laan, Maris
    Klopp, Norman
    Hillege, Hans L.
    Kloiber, Stefan
    Choi, Hyon
    Pirastu, Mario
    Tore, Silvia
    Probst-Hensch, Nicole M.
    Voelzke, Henry
    Gudnason, Vilmundur
    Parsa, Afshin
    Schmidt, Reinhold
    Whitfield, John B.
    Fornage, Myriam
    Gasparini, Paolo
    Siscovick, David S.
    Polasek, Ozren
    Campbell, Harry
    Rudan, Igor
    Bouatia-Naji, Nabila
    Metspalu, Andres
    Loos, Ruth J. F.
    van Duijn, Cornelia M.
    Borecki, Ingrid B.
    Ferrucci, Luigi
    Gambaro, Giovanni
    Deary, Ian J.
    Wolffenbuttel, Bruce H. R.
    Chambers, John C.
    Maerz, Winfried
    Pramstaller, Peter P.
    Snieder, Harold
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Wright, Alan F.
    Navis, Gerjan
    Watkins, Hugh
    Witteman, Jacqueline C. M.
    Sanna, Serena
    Schipf, Sabine
    Dunlop, Malcolm G.
    Toenjes, Anke
    Ripatti, Samuli
    Soranzo, Nicole
    Toniolo, Daniela
    Chasman, Daniel I.
    Raitakari, Olli
    Kao, W. H. Linda
    Ciullo, Marina
    Fox, Caroline S.
    Caulfield, Mark
    Bochud, Murielle
    Gieger, Christian
    Genome-wide association analyses identify 18 new loci associated with serum urate concentrations2013Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, nr 2, s. 145-154Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SEMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

  • 122. Kolz, Melanie
    et al.
    Johnson, Toby
    Sanna, Serena
    Teumer, Alexander
    Vitart, Veronique
    Perola, Markus
    Mangino, Massimo
    Albrecht, Eva
    Wallace, Chris
    Farrall, Martin
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Nyholt, Dale R
    Aulchenko, Yurii
    Beckmann, Jacques S
    Bergmann, Sven
    Bochud, Murielle
    Brown, Morris
    Campbell, Harry
    Connell, John
    Dominiczak, Anna
    Homuth, Georg
    Lamina, Claudia
    McCarthy, Mark I
    Meitinger, Thomas
    Mooser, Vincent
    Munroe, Patricia
    Nauck, Matthias
    Peden, John
    Prokisch, Holger
    Salo, Perttu
    Salomaa, Veikko
    Samani, Nilesh J
    Schlessinger, David
    Uda, Manuela
    Völker, Uwe
    Waeber, Gérard
    Waterworth, Dawn
    Wang-Sattler, Rui
    Wright, Alan F
    Adamski, Jerzy
    Whitfield, John B
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Wilson, James F
    Rudan, Igor
    Pramstaller, Peter
    Watkins, Hugh
    Doering, Angela
    Wichmann, H-Erich
    Spector, Tim D
    Peltonen, Leena
    Völzke, Henry
    Nagaraja, Ramaiah
    Vollenweider, Peter
    Caulfield, Mark
    Illig, Thomas
    Gieger, Christian
    Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations2009Inngår i: PLoS genetics, ISSN 1553-7404, Vol. 5, nr 6, s. e1000504-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2×10−201), ABCG2 (p = 3.1×10−26), SLC17A1 (p = 3.0×10−14), SLC22A11 (p = 6.7×10−14), SLC22A12 (p = 2.0×10−9), SLC16A9 (p = 1.1×10−8), GCKR (p = 1.4×10−9), LRRC16A (p = 8.5×10−9), and near PDZK1 (p = 2.7×10−9). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0×10−26) and propionyl-L-carnitine (p = 5.0×10−8) concentrations, which in turn were associated with serum UA levels (p = 1.4×10−57 and p = 8.1×10−54, respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels.

  • 123. Kulmala, Satu-Maria A.
    et al.
    Shabalova, Irena P.
    Petrovitchev, Nikolay
    Syrjänen, Kari J.
    Gyllensten, Ulf B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Johansson, Bo C.
    Syrjänen, Stina M.
    Tosi, P.
    Type-specific persistence of high-risk human papillomavirus infections in the New Independent States of the former Soviet Union Cohort Study2007Inngår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 16, nr 1, s. 17-22Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Prospective follow-up studies have recently suggested that persistent high-risk human papillomavirus (HPV) infections play a key role in the progression of CIN lesions and in the development of cervical cancer. However, data on type-specific persistence, viral integration, and the role of multiple infections are scanty.

    Materials and Methods: A cross-sectional/cohort study was conducted between 1998 and 2002 in three New Independent States of the former Soviet Union comprising a cohort of 3,187 women, of whom 854 women were followed up for a mean of 17 months (SD, 11.6). HPV genotyping was done with real-time PCR, detecting HPV types 16, 18/45, 31, 33/52/58, 35, and 39. The integration status of HPV16 was examined by using a novel Taqman-based PCR method.

    Results: The mean clearance time for the individual high– risk–type infection was 16.5 months (range = 0.9-34.9 months). HPV16 and HPV31 were the most persistent infections (clearance times = 18.1 and 16.2 months, respectively), whereas HPV39 infections cleared most rapidly. The mean copies per cell in HPV18/45, HPV31, HPV33/52/58, and HPV39 infections were higher in persisting HPV infections than in HPV infections that cleared, but the difference was not significant. Integration of HPV16 was not found to correlate with HPV persistence.

    Conclusions: A large proportion of women remained high-risk HPV positive after 18 months. Coinfection with multiple HPV types, viral load, or integration status did not correlate with persistence of high-risk HPV infections.

  • 124. Kulmala, Satu-Maria A.
    et al.
    Shabalova, Irena P.
    Petrovitchev, Nikolay
    Syrjänen, Kari J.
    Gyllensten, Ulf B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Syrjänen, Stina M.
    Prevalence of the most common high-risk HPV genotypes among women in three new independent states of the former Soviet Union2007Inngår i: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 79, nr 6, s. 771-781Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Type distribution of HPV has been studied in different geographic regions, but the data are scanty from the new independent states of the former Soviet Union. Here the HPV prevalence and distribution of the most frequent high-risk HPV types among 3,187 women at different risk for HPV and cervical intraepithelial neoplasia in Russia, Belarus, and Latvia is reported. HPV detection, type distribution and viral load analysis in DNA samples from cervical scrapes were done with real-time PCR-based assay detecting HPV types 16, 18, 31, 33, 35, 39, 45, 52, and 58. The overall HPV prevalence was 31.2%, HPV16 was the most prevalent type followed by HPV31 and HPV33 group. The overall HPV prevalences in Russia, Belarus and Latvia were 33.4%, 27.5%, and 26.2%. The type distributions were similar in these countries, except for Latvia where HPV39 was the third prevalent genotype. HPV prevalence was highest (40.8%) among women from sexually transmitted disease clinic, followed by 30.9% among gynecological outpatients and 27.2% in screening patients. HPV detection increased with cytological abnormality (P = 0.0001) and lesion grade in the biopsy (P = 0.0001), from 27% to 72% in normal samples to cancer, and from 64% to 77% in cervical intraepithelial neoplasia 1 to cancer. The normalized viral loads varied greatly between and among different HPV-types. The mean log HPV33 group copies/cell increased from negative for intraepithelial lesions to cancer (P = 0.049). Distribution of the most common high-risk HPV-types seems to be similar in these countries as reported in other major geographical regions.

  • 125. Kulmala, S-M A
    et al.
    Syrjänen, S M
    Gyllensten, Ulf B
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Shabalova, I P
    Petrovichev, N
    Tosi, P
    Syrjänen, K J
    Johansson, B C
    Early integration of high copy HPV16 detectable in women with normal and low grade cervical cytology and histology.2006Inngår i: J Clin Pathol, ISSN 0021-9746, Vol. 59, nr 5, s. 513-7Artikkel i tidsskrift (Fagfellevurdert)
  • 126. Lauc, Gordan
    et al.
    Huffman, Jennifer E.
    Pucic, Maja
    Zgaga, Lina
    Adamczyk, Barbara
    Muzinic, Ana
    Novokmet, Mislav
    Polasek, Ozren
    Gornik, Olga
    Kristic, Jasminka
    Keser, Toma
    Vitart, Veronique
    Scheijen, Blanca
    Uh, Hae-Won
    Molokhia, Mariam
    Patrick, Alan Leslie
    McKeigue, Paul
    Kolcic, Ivana
    Lukic, Ivan Kresimir
    Swann, Olivia
    van Leeuwen, Frank N.
    Ruhaak, L. Renee
    Houwing-Duistermaat, Jeanine J.
    Slagboom, P. Eline
    Beekman, Marian
    de Craen, Anton J. M.
    Deelder, Andre M.
    Zeng, Qiang
    Wang, Wei
    Hastie, Nicholas D.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wilson, James F.
    Wuhrer, Manfred
    Wright, Alan F.
    Rudd, Pauline M.
    Hayward, Caroline
    Aulchenko, Yurii
    Campbell, Harry
    Rudan, Igor
    Loci Associated with N-Glycosylation of Human Immunoglobulin G Show Pleiotropy with Autoimmune Diseases and Haematological Cancers2013Inngår i: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, nr 1, s. e1003225-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glycosylation of immunoglobulin G (IgG) influences IgG effector function by modulating binding to Fc receptors. To identify genetic loci associated with IgG glycosylation, we quantitated N-linked IgG glycans using two approaches. After isolating IgG from human plasma, we performed 77 quantitative measurements of N-glycosylation using ultra-performance liquid chromatography (UPLC) in 2,247 individuals from four European discovery populations. In parallel, we measured IgG N-glycans using MALDI-TOF mass spectrometry (MS) in a replication cohort of 1,848 Europeans. Meta-analysis of genome-wide association study (GWAS) results identified 9 genome-wide significant loci (P<2.27x10(-9)) in the discovery analysis and two of the same loci (B4GALT1 and MGAT3) in the replication cohort. Four loci contained genes encoding glycosyltransferases (ST6GAL1, B4GALT1, FUT8, and MGAT3), while the remaining 5 contained genes that have not been previously implicated in protein glycosylation (IKZF1, IL6ST-ANKRD55, ABCF2-SMARCD3, SUV420H1, and SMARCB1-DERL3). However, most of them have been strongly associated with autoimmune and inflammatory conditions (e. g., systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, Crohn's disease, diabetes type 1, multiple sclerosis, Graves' disease, celiac disease, nodular sclerosis) and/or haematological cancers (acute lymphoblastic leukaemia, Hodgkin lymphoma, and multiple myeloma). Follow-up functional experiments in haplodeficient Ikzf1 knock-out mice showed the same general pattern of changes in IgG glycosylation as identified in the meta-analysis. As IKZF1 was associated with multiple IgG N-glycan traits, we explored biomarker potential of affected N-glycans in 101 cases with SLE and 183 matched controls and demonstrated substantial discriminative power in a ROC-curve analysis (area under the curve=0.842). Our study shows that it is possible to identify new loci that control glycosylation of a single plasma protein using GWAS. The results may also provide an explanation for the reported pleiotropy and antagonistic effects of loci involved in autoimmune diseases and haematological cancer.

  • 127. Levovitz, Chaya
    et al.
    Chen, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ivansson, Emma
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Finnigan, John P
    Alshawish, Sara
    Zhang, Weijia
    Schadt, Eric E
    Posner, Marshal R
    Genden, Eric M
    Boffetta, Paolo
    Sikora, Andrew G
    TGFβ Receptor 1: An Immune Susceptibility Gene in HPV-Associated Cancer2014Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, nr 23, s. 6833-6844Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Only a minority of those exposed to human papillomavirus (HPV) develop HPV-related cervical and oropharyngeal cancer. Because host immunity affects infection and progression to cancer, we tested the hypothesis that genetic variation in immune-related genes is a determinant of susceptibility to oropharyngeal cancer and other HPV-associated cancers by performing a multitier integrative computational analysis with oropharyngeal cancer data from a head and neck cancer genome-wide association study (GWAS). Independent analyses, including single-gene, gene-interconnectivity, protein-protein interaction, gene expression, and pathway analysis, identified immune genes and pathways significantly associated with oropharyngeal cancer. TGFβR1, which intersected all tiers of analysis and thus selected for validation, replicated significantly in the head and neck cancer GWAS limited to HPV-seropositive cases and an independent cervical cancer GWAS. The TGFβR1 containing p38-MAPK pathway was significantly associated with oropharyngeal cancer and cervical cancer, and TGFβR1 was overexpressed in oropharyngeal cancer, cervical cancer, and HPV(+) head and neck cancer tumors. These concordant analyses implicate TGFβR1 signaling as a process dysregulated across HPV-related cancers. This study demonstrates that genetic variation in immune-related genes is associated with susceptibility to oropharyngeal cancer and implicates TGFβR1/TGFβ signaling in the development of both oropharyngeal cancer and cervical cancer. Better understanding of the immunogenetic basis of susceptibility to HPV-associated cancers may provide insight into host/virus interactions and immune processes dysregulated in the minority of HPV-exposed individuals who progress to cancer. Cancer Res; 74(23); 6833-44.

  • 128. Levovitz, Chaya
    et al.
    Chen, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Ivansson, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Mckay, James
    Brennan, Paul
    Boffetta, Paolo
    Sikora, Andrew
    TGFBR1 and other immune-related genes modify susceptibility to HPV-associated head and neck cancer2014Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, nr 19Artikkel i tidsskrift (Annet vitenskapelig)
  • 129.
    Lindström, Annika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning Dalarna. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa. Örebro Univ, Clin Res Ctr, Fac Med & Hlth, Örebro, Sweden.
    Sanchez Hermansson, Ruth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi. Örebro Univ, Fac Med & Hlth, Dept Oncol, Örebro, Sweden.
    Gustavsson, Inger M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Lindberg, Julia Hedlund
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Gyllensten, Ulf B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Olovsson, Matts
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Cervical dysplasia in elderly women performing repeated self-sampling for HPV testing2018Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 12, artikkel-id e0207714Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background About 30% of the cervical cancer cases in Sweden occur in women older than 60. The primary aim was to evaluate the acceptability of repeated self-sampling at home for HPV-testing in elderly women. The prevalence of HPV and HPV related dysplasia as well as the sensitivity of cytology was evaluated. Methods Repeated self-sampling at home for HPV testing was offered 375 women in each of the four age groups 60, 65, 70 and 75 years. Women with two consecutive positive HPV tests were examined with sampling for histology and cytology. Findings A self-sample was provided by 59.5% (893/1500) of the invited women. The overall prevalence of HPV was 4.4% (95% CI 3.2-6.0, n = 39) in the first test, and 2.5% were persistent positive in the second test (95% C 1.6-3.8, n = 22) collected on average 5.5 months later. Dysplasia, was found in 1.8% (16/893) (95% CI 1.1-3.0) and CIN 2+ in 1.0% (9/893) (95% CI 0.5-2.0) of the women. Of the 16 women with dysplasia in histology, 13 (81.2%) had a normal cytology. Interpretation Repeated self-sampling at home combined with HPV testing was well accepted among elderly women. A high prevalence of CIN was diagnosed by histology. Cytology showed extremely low sensitivity and should not be recommended for this age group.

  • 130. Locke, Adam E
    et al.
    Kahali, Bratati
    Berndt, Sonja I
    Justice, Anne E
    Pers, Tune H
    Day, Felix R
    Powell, Corey
    Vedantam, Sailaja
    Buchkovich, Martin L
    Yang, Jian
    Croteau-Chonka, Damien C
    Esko, Tonu
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ferreira, Teresa
    Gustafsson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kutalik, Zoltán
    Luan, Jian'an
    Mägi, Reedik
    Randall, Joshua C
    Winkler, Thomas W
    Wood, Andrew R
    Workalemahu, Tsegaselassie
    Faul, Jessica D
    Smith, Jennifer A
    Hua Zhao, Jing
    Zhao, Wei
    Chen, Jin
    Fehrmann, Rudolf
    Hedman, Åsa K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Karjalainen, Juha
    Schmidt, Ellen M
    Absher, Devin
    Amin, Najaf
    Anderson, Denise
    Beekman, Marian
    Bolton, Jennifer L
    Bragg-Gresham, Jennifer L
    Buyske, Steven
    Demirkan, Ayse
    Deng, Guohong
    Ehret, Georg B
    Feenstra, Bjarke
    Feitosa, Mary F
    Fischer, Krista
    Goel, Anuj
    Gong, Jian
    Jackson, Anne U
    Kanoni, Stavroula
    Kleber, Marcus E
    Kristiansson, Kati
    Lim, Unhee
    Lotay, Vaneet
    Mangino, Massimo
    Mateo Leach, Irene
    Medina-Gomez, Carolina
    Medland, Sarah E
    Nalls, Michael A
    Palmer, Cameron D
    Pasko, Dorota
    Pechlivanis, Sonali
    Peters, Marjolein J
    Prokopenko, Inga
    Shungin, Dmitry
    Stančáková, Alena
    Strawbridge, Rona J
    Ju Sung, Yun
    Tanaka, Toshiko
    Teumer, Alexander
    Trompet, Stella
    van der Laan, Sander W
    van Setten, Jessica
    Van Vliet-Ostaptchouk, Jana V
    Wang, Zhaoming
    Yengo, Loïc
    Zhang, Weihua
    Isaacs, Aaron
    Albrecht, Eva
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Arscott, Gillian M
    Attwood, Antony P
    Bandinelli, Stefania
    Barrett, Amy
    Bas, Isabelita N
    Bellis, Claire
    Bennett, Amanda J
    Berne, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Blagieva, Roza
    Blüher, Matthias
    Böhringer, Stefan
    Bonnycastle, Lori L
    Böttcher, Yvonne
    Boyd, Heather A
    Bruinenberg, Marcel
    Caspersen, Ida H
    Ida Chen, Yii-Der
    Clarke, Robert
    Warwick Daw, E
    de Craen, Anton J M
    Delgado, Graciela
    Dimitriou, Maria
    Doney, Alex S F
    Eklund, Niina
    Estrada, Karol
    Eury, Elodie
    Folkersen, Lasse
    Fraser, Ross M
    Garcia, Melissa E
    Geller, Frank
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Gigante, Bruna
    Go, Alan S
    Golay, Alain
    Goodall, Alison H
    Gordon, Scott D
    Gorski, Mathias
    Grabe, Hans-Jörgen
    Grallert, Harald
    Grammer, Tanja B
    Gräßler, Jürgen
    Grönberg, Henrik
    Groves, Christopher J
    Gusto, Gaëlle
    Haessler, Jeffrey
    Hall, Per
    Haller, Toomas
    Hallmans, Goran
    Hartman, Catharina A
    Hassinen, Maija
    Hayward, Caroline
    Heard-Costa, Nancy L
    Helmer, Quinta
    Hengstenberg, Christian
    Holmen, Oddgeir
    Hottenga, Jouke-Jan
    James, Alan L
    Jeff, Janina M
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jolley, Jennifer
    Juliusdottir, Thorhildur
    Kinnunen, Leena
    Koenig, Wolfgang
    Koskenvuo, Markku
    Kratzer, Wolfgang
    Laitinen, Jaana
    Lamina, Claudia
    Leander, Karin
    Lee, Nanette R
    Lichtner, Peter
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lindström, Jaana
    Sin Lo, Ken
    Lobbens, Stéphane
    Lorbeer, Roberto
    Lu, Yingchang
    Mach, François
    Magnusson, Patrik K E
    Mahajan, Anubha
    McArdle, Wendy L
    McLachlan, Stela
    Menni, Cristina
    Merger, Sigrun
    Mihailov, Evelin
    Milani, Lili
    Moayyeri, Alireza
    Monda, Keri L
    Morken, Mario A
    Mulas, Antonella
    Müller, Gabriele
    Müller-Nurasyid, Martina
    Musk, Arthur W
    Nagaraja, Ramaiah
    Nöthen, Markus M
    Nolte, Ilja M
    Pilz, Stefan
    Rayner, Nigel W
    Renstrom, Frida
    Rettig, Rainer
    Ried, Janina S
    Ripke, Stephan
    Robertson, Neil R
    Rose, Lynda M
    Sanna, Serena
    Scharnagl, Hubert
    Scholtens, Salome
    Schumacher, Fredrick R
    Scott, William R
    Seufferlein, Thomas
    Shi, Jianxin
    Vernon Smith, Albert
    Smolonska, Joanna
    Stanton, Alice V
    Steinthorsdottir, Valgerdur
    Stirrups, Kathleen
    Stringham, Heather M
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Swertz, Morris A
    Swift, Amy J
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tan, Sian-Tsung
    Tayo, Bamidele O
    Thorand, Barbara
    Thorleifsson, Gudmar
    Tyrer, Jonathan P
    Uh, Hae-Won
    Vandenput, Liesbeth
    Verhulst, Frank C
    Vermeulen, Sita H
    Verweij, Niek
    Vonk, Judith M
    Waite, Lindsay L
    Warren, Helen R
    Waterworth, Dawn
    Weedon, Michael N
    Wilkens, Lynne R
    Willenborg, Christina
    Wilsgaard, Tom
    Wojczynski, Mary K
    Wong, Andrew
    Wright, Alan F
    Zhang, Qunyuan
    Brennan, Eoin P
    Choi, Murim
    Dastani, Zari
    Drong, Alexander W
    Eriksson, Per
    Franco-Cereceda, Anders
    Gådin, Jesper R
    Gharavi, Ali G
    Goddard, Michael E
    Handsaker, Robert E
    Huang, Jinyan
    Karpe, Fredrik
    Kathiresan, Sekar
    Keildson, Sarah
    Kiryluk, Krzysztof
    Kubo, Michiaki
    Lee, Jong-Young
    Liang, Liming
    Lifton, Richard P
    Ma, Baoshan
    McCarroll, Steven A
    McKnight, Amy J
    Min, Josine L
    Moffatt, Miriam F
    Montgomery, Grant W
    Murabito, Joanne M
    Nicholson, George
    Nyholt, Dale R
    Okada, Yukinori
    Perry, John R B
    Dorajoo, Rajkumar
    Reinmaa, Eva
    Salem, Rany M
    Sandholm, Niina
    Scott, Robert A
    Stolk, Lisette
    Takahashi, Atsushi
    Tanaka, Toshihiro
    Van't Hooft, Ferdinand M
    Vinkhuyzen, Anna A E
    Westra, Harm-Jan
    Zheng, Wei
    Zondervan, Krina T
    Heath, Andrew C
    Arveiler, Dominique
    Bakker, Stephan J L
    Beilby, John
    Bergman, Richard N
    Blangero, John
    Bovet, Pascal
    Campbell, Harry
    Caulfield, Mark J
    Cesana, Giancarlo
    Chakravarti, Aravinda
    Chasman, Daniel I
    Chines, Peter S
    Collins, Francis S
    Crawford, Dana C
    Adrienne Cupples, L
    Cusi, Daniele
    Danesh, John
    de Faire, Ulf
    den Ruijter, Hester M
    Dominiczak, Anna F
    Erbel, Raimund
    Erdmann, Jeanette
    Eriksson, Johan G
    Farrall, Martin
    Felix, Stephan B
    Ferrannini, Ele
    Ferrières, Jean
    Ford, Ian
    Forouhi, Nita G
    Forrester, Terrence
    Franco, Oscar H
    Gansevoort, Ron T
    Gejman, Pablo V
    Gieger, Christian
    Gottesman, Omri
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hall, Alistair S
    Harris, Tamara B
    Hattersley, Andrew T
    Hicks, Andrew A
    Hindorff, Lucia A
    Hingorani, Aroon D
    Hofman, Albert
    Homuth, Georg
    Kees Hovingh, G
    Humphries, Steve E
    Hunt, Steven C
    Hyppönen, Elina
    Illig, Thomas
    Jacobs, Kevin B
    Jarvelin, Marjo-Riitta
    Jöckel, Karl-Heinz
    Johansen, Berit
    Jousilahti, Pekka
    Wouter Jukema, J
    Jula, Antti M
    Kaprio, Jaakko
    Kastelein, John J P
    Keinanen-Kiukaanniemi, Sirkka M
    Kiemeney, Lambertus A
    Knekt, Paul
    Kooner, Jaspal S
    Kooperberg, Charles
    Kovacs, Peter
    Kraja, Aldi T
    Kumari, Meena
    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
    Moll, Frans L
    Morris, Andrew D
    Morris, Andrew P
    Murray, Jeffrey C
    Nelis, Mari
    Ohlsson, Claes
    Oldehinkel, Albertine J
    Ong, Ken K
    Madden, Pamela A F
    Pasterkamp, Gerard
    Peden, John F
    Peters, Annette
    Postma, Dirkje S
    Pramstaller, Peter P
    Price, Jackie F
    Qi, Lu
    Raitakari, Olli T
    Rankinen, Tuomo
    Rao, D C
    Rice, Treva K
    Ridker, Paul M
    Rioux, John D
    Ritchie, Marylyn D
    Rudan, Igor
    Salomaa, Veikko
    Samani, Nilesh J
    Saramies, Jouko
    Sarzynski, Mark A
    Schunkert, Heribert
    Schwarz, Peter E H
    Sever, Peter
    Shuldiner, Alan R
    Sinisalo, Juha
    Stolk, Ronald P
    Strauch, Konstantin
    Tönjes, Anke
    Trégouët, David-Alexandre
    Tremblay, Angelo
    Tremoli, Elena
    Virtamo, Jarmo
    Vohl, Marie-Claude
    Völker, Uwe
    Waeber, Gérard
    Willemsen, Gonneke
    Witteman, Jacqueline C
    Zillikens, M Carola
    Adair, Linda S
    Amouyel, Philippe
    Asselbergs, Folkert W
    Assimes, Themistocles L
    Bochud, Murielle
    Boehm, Bernhard O
    Boerwinkle, Eric
    Bornstein, Stefan R
    Bottinger, Erwin P
    Bouchard, Claude
    Cauchi, Stéphane
    Chambers, John C
    Chanock, Stephen J
    Cooper, Richard S
    de Bakker, Paul I W
    Dedoussis, George
    Ferrucci, Luigi
    Franks, Paul W
    Froguel, Philippe
    Groop, Leif C
    Haiman, Christopher A
    Hamsten, Anders
    Hui, Jennie
    Hunter, David J
    Hveem, Kristian
    Kaplan, Robert C
    Kivimaki, Mika
    Kuh, Diana
    Laakso, Markku
    Liu, Yongmei
    Martin, Nicholas G
    März, Winfried
    Melbye, Mads
    Metspalu, Andres
    Moebus, Susanne
    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
    Sattar, Naveed
    Schadt, Eric E
    Schlessinger, David
    Eline Slagboom, P
    Snieder, Harold
    Spector, Tim D
    Thorsteinsdottir, Unnur
    Stumvoll, Michael
    Tuomilehto, Jaakko
    Uitterlinden, André G
    Uusitupa, Matti
    van der Harst, Pim
    Walker, Mark
    Wallaschofski, Henri
    Wareham, Nicholas J
    Watkins, Hugh
    Weir, David R
    Wichmann, H-Erich
    Wilson, James F
    Zanen, Pieter
    Borecki, Ingrid B
    Deloukas, Panos
    Fox, Caroline S
    Heid, Iris M
    O'Connell, Jeffrey R
    Strachan, David P
    Stefansson, Kari
    van Duijn, Cornelia M
    Abecasis, Gonçalo R
    Franke, Lude
    Frayling, Timothy M
    McCarthy, Mark I
    Visscher, Peter M
    Scherag, André
    Willer, Cristen J
    Boehnke, Michael
    Mohlke, Karen L
    Lindgren, Cecilia M
    Beckmann, Jacques S
    Barroso, Inês
    North, Kari E
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hirschhorn, Joel N
    Loos, Ruth J F
    Speliotes, Elizabeth K
    Genetic studies of body mass index yield new insights for obesity biology2015Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 518, nr 7538, s. 197-206Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

  • 131.
    Lopes, Fatima
    et al.
    Univ Minho, Life & Hlth Sci Res Inst ICVS, Sch Hlth Sci, P-4710057 Braga, Portugal.;ICVS 3Bs PT Govt Associate Lab, Braga, Portugal..
    Barbosa, Mafalda
    Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, Mindich Child Hlth & Dev Inst, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA.;Inst Gulbenkian Ciencias, Oeiras, Portugal..
    Ameur, Adam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Soares, Gabriela
    Ctr Hosp Porto, Ctr Med Genet Dr Jacinto Magalhaes, Oporto, Portugal..
    de Sa, Joaquim
    Ctr Hosp & Univ Coimbra, Hosp Pediat, Serv Genet Med, Coimbra, Portugal..
    Dias, Ana Isabel
    Ctr Hosp Lisboa Cent, Hosp D Estefania, Serv Neurol Pediat, Lisbon, Portugal..
    Oliveira, Guiomar
    Ctr Hosp & Univ Coimbra, Hosp Pediat, Unidade Neurodesenvolvimento & Autismo, Ctr Desenvolvimento Crianca, Coimbra, Portugal.;Ctr Hosp & Univ Coimbra, Hosp Pediat, Ctr Invest & Formacao Clin, Coimbra, Portugal.;Univ Coimbra, Univ Clin Pediat, Fac Med, Coimbra, Portugal.;Univ Coimbra, Inst Biomed Imaging & Life Sci, Coimbra, Portugal..
    Cabral, Pedro
    Egas Moniz Hosp, Dept Neurol, Lisbon, Portugal..
    Temudo, Teresa
    Ctr Hosp Porto, Dept Neuropediat, Oporto, Portugal..
    Calado, Eulalia
    Ctr Hosp Lisboa Cent, Hosp D Estefania, Serv Neurol Pediat, Lisbon, Portugal..
    Cruz, Isabel Fineza
    Ctr Hosp Univ Coimbra, Ctr Desenvolvimento Luis Borges, Hosp Pediat, Coimbra, Portugal..
    Vieira, Jose Pedro
    Ctr Hosp Lisboa Cent, Hosp D Estefania, Serv Neurol Pediat, Lisbon, Portugal..
    Oliveira, Renata
    Ctr Hosp & Univ Coimbra, Hosp Pediat, Serv Genet Med, Coimbra, Portugal..
    Esteves, Sofia
    Univ Minho, Life & Hlth Sci Res Inst ICVS, Sch Hlth Sci, P-4710057 Braga, Portugal.;ICVS 3Bs PT Govt Associate Lab, Braga, Portugal..
    Sauer, Sascha
    Max Planck Inst Mol Genet, Otto Warburg Lab, Ihnestr 73, D-14195 Berlin, Germany.;Univ Wurzburg, CU Syst Med, D-97070 Wurzburg, Germany..
    Jonasson, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala Univ, Mol Med & Sci Life Lab, Dept Med Sci, Uppsala, Sweden..
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Pinto, Dalila
    Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, Mindich Child Hlth & Dev Inst, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA..
    Maciel, Patricia
    Univ Minho, Life & Hlth Sci Res Inst ICVS, Sch Hlth Sci, P-4710057 Braga, Portugal.;ICVS 3Bs PT Govt Associate Lab, Braga, Portugal..
    Identification of novel genetic causes of Rett syndrome-like phenotypes2016Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 53, nr 3, s. 190-199Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background The aim of this work was to identify new genetic causes of Rett-like phenotypes using array comparative genomic hybridisation and a whole exome sequencing approach. Methods and results We studied a cohort of 19 Portuguese patients (16 girls, 3 boys) with a clinical presentation significantly overlapping Rett syndrome (RTT). Genetic analysis included filtering of the single nucleotide variants and indels with preference for de novo, homozygous/compound heterozygous, or maternally inherited X linked variants. Examination by MRI and muscle biopsies was also performed. Pathogenic genomic imbalances were found in two patients (10.5%): an 18q21.2 deletion encompassing four exons of the TCF4 gene and a mosaic UPD of chromosome 3. Variants in genes previously implicated in neurodevelopmental disorders (NDD) were identified in six patients (32%): de novo variants in EEF1A2, STXBP1 and ZNF238 were found in three patients, maternally inherited X linked variants in SLC35A2, ZFX and SHROOM4 were detected in two male patients and one homozygous variant in EIF2B2 was detected in one patient. Variants were also detected in five novel NDD candidate genes (26%): we identified de novo variants in the RHOBTB2, SMARCA1 and GABBR2 genes; a homozygous variant in EIF4G1; compound heterozygous variant in HTT. Conclusions Network analysis reveals that these genes interact by means of protein interactions with each other and with the known RTT genes. These findings expand the phenotypical spectrum of previously known NDD genes to encompass RTT-like clinical presentations and identify new candidate genes for RTT-like phenotypes.

  • 132.
    Lopes, Fatima
    et al.
    Univ Minho, Sch Hlth Sci, Life & Hlth Sci Res Inst ICVS, Braga, Portugal.;ICVS 3Bs PT Govt Associate Lab, Braga, Portugal..
    Barbosa, Mafalda
    Mt Sinai Sch Med, Mindich Child Hlth & Dev Inst, Seaver Autism Ctr, Dept Psychiat, New York, NY USA.;Mt Sinai Sch Med, Mindich Child Hlth & Dev Inst, Seaver Autism Ctr, Dept Genet & Genom Sci, New York, NY USA..
    Temudo, Teresa
    Hosp Geral St Antonio, Oporto, Portugal..
    de Sa, Joaquim
    Hosp Pediat Coimbra, Serv Genet Med, Coimbra, Portugal..
    Dias, Ana Isabel
    Hosp Dona Estefania, Lisbon, Portugal..
    Oliveira, Guiomar
    Hosp Pediat Coimbra, Ctr Desenvolvimento Crianca, Coimbra, Portugal..
    Cabra, Pedro
    Hosp S Francisco Xavier, Lisbon, Portugal..
    Calado, Eulalia
    Hosp Dona Estefania, Lisbon, Portugal..
    Cruz, Isabel Fineza
    Hosp Pediat Coimbra, Ctr Desenvolvimento Crianca, Coimbra, Portugal..
    Soares, Gabriela
    Mt Sinai Sch Med, Mindich Child Hlth & Dev Inst, Seaver Autism Ctr, Dept Psychiat, New York, NY USA.;Mt Sinai Sch Med, Mindich Child Hlth & Dev Inst, Seaver Autism Ctr, Dept Genet & Genom Sci, New York, NY USA..
    Vieira, Jose Pedro
    Hosp Dona Estefania, Lisbon, Portugal..
    Venancio, Maria Margarida
    Hosp Pediat Coimbra, Serv Genet Med, Coimbra, Portugal..
    Oliveira, Renata
    Hosp Pediat Coimbra, Serv Genet Med, Coimbra, Portugal..
    Jonasson, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ameur, Adam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pinto, Dalila
    Mt Sinai Sch Med, Mindich Child Hlth & Dev Inst, Seaver Autism Ctr, Dept Psychiat, New York, NY USA.;Mt Sinai Sch Med, Mindich Child Hlth & Dev Inst, Seaver Autism Ctr, Dept Genet & Genom Sci, New York, NY USA..
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Maciel, Patricia
    Univ Minho, Sch Hlth Sci, Life & Hlth Sci Res Inst ICVS, Braga, Portugal.;ICVS 3Bs PT Govt Associate Lab, Braga, Portugal..
    Identification of novel genetic causes of Rett syndrome-like phenotypes by whole exome sequencing2015Inngår i: International Journal of Developmental Neuroscience, ISSN 0736-5748, E-ISSN 1873-474X, Vol. 47, s. 99-99Artikkel i tidsskrift (Annet vitenskapelig)
  • 133. Loth, Daan W
    et al.
    Artigas, María Soler
    Gharib, Sina A
    Wain, Louise V
    Franceschini, Nora
    Koch, Beate
    Pottinger, Tess D
    Smith, Albert Vernon
    Duan, Qing
    Oldmeadow, Chris
    Lee, Mi Kyeong
    Strachan, David P
    James, Alan L
    Huffman, Jennifer E
    Vitart, Veronique
    Ramasamy, Adaikalavan
    Wareham, Nicholas J
    Kaprio, Jaakko
    Wang, Xin-Qun
    Trochet, Holly
    Kähönen, Mika
    Flexeder, Claudia
    Albrecht, Eva
    Lopez, Lorna M
    de Jong, Kim
    Thyagarajan, Bharat
    Alves, Alexessander Couto
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Omenaas, Ernst
    Joshi, Peter K
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Viñuela, Ana
    Launer, Lenore J
    Loehr, Laura R
    Fornage, Myriam
    Li, Guo
    Wilk, Jemma B
    Tang, Wenbo
    Manichaikul, Ani
    Lahousse, Lies
    Harris, Tamara B
    North, Kari E
    Rudnicka, Alicja R
    Hui, Jennie
    Gu, Xiangjun
    Lumley, Thomas
    Wright, Alan F
    Hastie, Nicholas D
    Campbell, Susan
    Kumar, Rajesh
    Pin, Isabelle
    Scott, Robert A
    Pietiläinen, Kirsi H
    Surakka, Ida
    Liu, Yongmei
    Holliday, Elizabeth G
    Schulz, Holger
    Heinrich, Joachim
    Davies, Gail
    Vonk, Judith M
    Wojczynski, Mary
    Pouta, Anneli
    Johansson, Åsa
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Wild, Sarah H
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rivadeneira, Fernando
    Völzke, Henry
    Hysi, Pirro G
    Eiriksdottir, Gudny
    Morrison, Alanna C
    Rotter, Jerome I
    Gao, Wei
    Postma, Dirkje S
    White, Wendy B
    Rich, Stephen S
    Hofman, Albert
    Aspelund, Thor
    Couper, David
    Smith, Lewis J
    Psaty, Bruce M
    Lohman, Kurt
    Burchard, Esteban G
    Uitterlinden, André G
    Garcia, Melissa
    Joubert, Bonnie R
    McArdle, Wendy L
    Musk, A Bill
    Hansel, Nadia
    Heckbert, Susan R
    Zgaga, Lina
    van Meurs, Joyce B J
    Navarro, Pau
    Rudan, Igor
    Oh, Yeon-Mok
    Redline, Susan
    Jarvis, Deborah L
    Zhao, Jing Hua
    Rantanen, Taina
    O'Connor, George T
    Ripatti, Samuli
    Scott, Rodney J
    Karrasch, Stefan
    Grallert, Harald
    Gaddis, Nathan C
    Starr, John M
    Wijmenga, Cisca
    Minster, Ryan L
    Lederer, David J
    Pekkanen, Juha
    Gyllensten, Ulf
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Campbell, Harry
    Morris, Andrew P
    Gläser, Sven
    Hammond, Christopher J
    Burkart, Kristin M
    Beilby, John
    Kritchevsky, Stephen B
    Gudnason, Vilmundur
    Hancock, Dana B
    Williams, O Dale
    Polasek, Ozren
    Zemunik, Tatijana
    Kolcic, Ivana
    Petrini, Marcy F
    Wjst, Matthias
    Kim, Woo Jin
    Porteous, David J
    Scotland, Generation
    Smith, Blair H
    Viljanen, Anne
    Heliövaara, Markku
    Attia, John R
    Sayers, Ian
    Hampel, Regina
    Gieger, Christian
    Deary, Ian J
    Boezen, H Marike
    Newman, Anne
    Jarvelin, Marjo-Riitta
    Wilson, James F
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Stricker, Bruno H
    Teumer, Alexander
    Spector, Timothy D
    Melén, Erik
    Peters, Marjolein J
    Lange, Leslie A
    Barr, R Graham
    Bracke, Ken R
    Verhamme, Fien M
    Sung, Joohon
    Hiemstra, Pieter S
    Cassano, Patricia A
    Sood, Akshay
    Hayward, Caroline
    Dupuis, Josée
    Hall, Ian P
    Brusselle, Guy G
    Tobin, Martin D
    London, Stephanie J
    Genome-wide association analysis identifies six new loci associated with forced vital capacity2014Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, s. 669-677Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

  • 134.
    Magnusson, Patrik K E
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Rasmussen, Finn
    Gyllensten, Ulf B
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Height at age 18 years is a strong predictor of attained education later in life: cohort study of over 950,000 Swedish men.2006Inngår i: Int J Epidemiol, ISSN 0300-5771, Vol. 35, nr 3, s. 658-63Artikkel i tidsskrift (Fagfellevurdert)
  • 135.
    Mansouri, Larry
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi.
    Gunnarsson, Rebeqa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi.
    Sutton, Lesley-Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi.
    Ameur, Adam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Hooper, Sean D.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Mayrhofer, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Juliusson, Gunnar
    Isaksson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi.
    Next generation RNA-sequencing in prognostic subsets of chronic lymphocytic leukemia2012Inngår i: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 87, nr 7, s. 737-740Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Advances in next-generation RNA-sequencing have revealed the complexity of transcriptomes by allowing both coding and noncoding (nc) RNAs to be analyzed. However, limited data exist regarding the whole transcriptional landscape of chronic lymphocytic leukemia (CLL). In this pilot-study, we evaluated RNA-sequencing in CLL by comparing two subsets which carry almost identical or `` stereotyped'' B-cell receptors with distinct clinical outcome, that is the poor-prognostic subset # 1 (n = 4) and the more favorable-prognostic subset # 4 (n = 4). Our analysis revealed that 156 genes (e.g. LPL, WNT9A) and 76 ncRNAs, (e. g. SNORD48, SNORD115) were differentially expressed between the subsets. This technology also enabled us to identify numerous subset-specific splice variants (n = 406), which were predominantly expressed in subset # 1, including a splice-isoform of MSI2 with a novel start exon. A further important application of RNA-sequencing was for mutation detection and revealed 16-30 missense mutations per sample; notably many of these changes were found in genes with a strong potential for involvement in CLL pathogenesis, e. g., ATM and NOTCH2. This study not only demonstrates the effectiveness of RNA-sequencing for identifying mutations, quantifying gene expression and detecting splicing events, but also highlights the potential such global approaches have to significantly advance our understanding of the molecular mechanisms behind CLL development. 

  • 136. Marincevic-Zuniga, Yanara
    et al.
    Gustavsson, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Multiply-primed rolling circle amplification of human papillomavirus using sequence-specific primers2012Inngår i: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 432, nr 1, s. 57-62Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Multiply-primed rolling circle amplification (RCA) is a suitable technique for amplification of circular templates and has been used to identify novel human papillomaviruses (HPV). In this study we develop an efficient RCA for whole genome amplification of HPV using HPV-specific primers in clinical samples and establish a protocol for whole genome sequencing using the Sanger method. Amplification of cloned HPV-genomes by RCA was compared using specific primers against random hexamers. Using HPV-specific primers increased the effectiveness on average 15.2 times and the enrichment of HPV relative to human gDNA on average 62.2 times, as compared to using random hexamer. RCA products were sequenced without need for cloning, even when using low-input amounts. The technique was successfully used on 4 patient samples from FTA cards, to generate whole HPV-genome sequences. Degenerated HPV-specific primers for RCA produce DNA of sufficient quality and quantity suitable for sequencing and other potential downstream analyses.

  • 137. Marroni, Fabio
    et al.
    Pfeufer, Arne
    Aulchenko, Yurii S.
    Franklin, Christopher S.
    Isaacs, Aaron
    Pichler, Irene
    Wild, Sarah H.
    Oostra, Ben A.
    Wright, Alan F.
    Campbell, Harry
    Witteman, Jacqueline C.
    Kääb, Stefan
    Hicks, Andrew A.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Rudan, Igor
    Meitinger, Thomas
    Pattaro, Cristian
    van Duijn, Cornelia M.
    Wilson, James F.
    Pramstaller, Peter P.
    A genome-wide association scan of RR and QT interval duration in 3 European genetically isolated populations: the EUROSPAN project2009Inngår i: Circulation: Cardiovascular Genetics, ISSN 1942-3268, Vol. 2, nr 4, s. 322-328Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: We set out to identify common genetic determinants of the length of the RR and QT intervals in 2325 individuals from isolated European populations. METHODS AND RESULTS: We analyzed the heart rate at rest, measured as the RR interval, and the length of the corrected QT interval for association with 318 237 single-nucleotide polymorphisms. The RR interval was associated with common variants within GPR133, a G-protein-coupled receptor (rs885389, P=3.9 x 10(-8)). The QT interval was associated with the earlier reported NOS1AP gene (rs2880058, P=2.00 x 10(-10)) and with a region on chromosome 13 (rs2478333, P=4.34 x 10(-8)), which is 100 kb from the closest known transcript LOC730174 and has previously not been associated with the length of the QT interval. CONCLUSIONS: Our results suggested an association between the RR interval and GPR133 and confirmed an association between the QT interval and NOS1AP.

  • 138. Mascalzoni, Deborah
    et al.
    Janssens, A. Cecile J. W.
    Stewart, Alison
    Pramstaller, Peter
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Rudan, Igor
    van Duijn, Cornelia M.
    Wilson, James F.
    Campbell, Harry
    Quillan, Ruth M. C.
    Comparison of participant information and informed consent forms of five European studies in genetic isolated populations2010Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 18, nr 3, s. 296-302Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Family-based research in genetically isolated populations is an effective approach for identifying loci influencing variation in disease traits. In common with all studies in humans, those in genetically isolated populations need ethical approval; however, existing ethical frameworks may be inadequate to protect participant privacy and confidentiality and to address participants' information needs in such populations. Using the ethical-legal guidelines of the Council for International Organizations of Medical Sciences (CIOMS) as a template, we compared the participant information leaflets and consent forms of studies in five European genetically isolated populations to identify additional information that should be incorporated into information leaflets and consent forms to guarantee satisfactorily informed consent. We highlight the additional information that participants require on the research purpose and the reasons why their population was chosen; on the potential risks and benefits of participation; on the opportunities for benefit sharing; on privacy; on the withdrawal of consent and on the disclosure of genetic data. This research raises some important issues that should be addressed properly and identifies relevant types of information that should be incorporated into information leaflets for this type of study.

  • 139. Mbulawa, Zizipho Z. A.
    et al.
    Johnson, Leigh F.
    Marais, Dianne J.
    Gustavsson, Inger
    Moodley, Jennifer R.
    Coetzee, David
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Williamson, Anna-Lise
    Increased alpha-9 human papillomavirus species viral load in human immunodeficiency virus positive women2014Inngår i: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 14, s. 51-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Persistent high-risk (HR) human papillomavirus (HPV) infection and increased HR-HPV viral load are associated with the development of cancer. This study investigated the effect of human immunodeficiency virus (HIV) co-infection, HIV viral load and CD4 count on the HR-HPV viral load; and also investigated the predictors of cervical abnormalities. Methods: Participants were 292 HIV-negative and 258 HIV-positive women. HR-HPV viral loads in cervical cells were determined by the real-time polymerase chain reaction. Results: HIV-positive women had a significantly higher viral load for combined alpha-9 HPV species compared to HIV-negative women (median 3.9 copies per cell compared to 0.63 copies per cell, P = 0.022). This was not observed for individual HPV types. HIV-positive women with CD4 counts > 350/mu l had significantly lower viral loads for alpha-7 HPV species (median 0.12 copies per cell) than HIV-positive women with CD4 = 350/mu l (median 1.52 copies per cell, P = 0.008), but low CD4 count was not significantly associated with increased viral load for other HPV species. High viral loads for alpha-6, alpha-7 and alpha-9 HPV species were significant predictors of abnormal cytology in women. Conclusion: HIV co-infection significantly increased the combined alpha-9 HPV viral load in women but not viral loads for individual HPV types. High HR-HPV viral load was associated with cervical abnormal cytology.

  • 140. McQuillan, Ruth
    et al.
    Eklund, Niina
    Pirastu, Nicola
    Kuningas, Maris
    McEvoy, Brian P
    Esko, Tõnu
    Corre, Tanguy
    Davies, Gail
    Kaakinen, Marika
    Lyytikäinen, Leo-Pekka
    Kristiansson, Kati
    Havulinna, Aki S
    Gögele, Martin
    Vitart, Veronique
    Tenesa, Albert
    Aulchenko, Yurii
    Hayward, Caroline
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Boban, Mladen
    Ulivi, Sheila
    Robino, Antonietta
    Boraska, Vesna
    Igl, Wilmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wild, Sarah H
    Zgaga, Lina
    Amin, Najaf
    Theodoratou, Evropi
    Polašek, Ozren
    Girotto, Giorgia
    Lopez, Lorna M
    Sala, Cinzia
    Lahti, Jari
    Laatikainen, Tiina
    Prokopenko, Inga
    Kals, Mart
    Viikari, Jorma
    Yang, Jian
    Pouta, Anneli
    Estrada, Karol
    Hofman, Albert
    Freimer, Nelson
    Martin, Nicholas G
    Kähönen, Mika
    Milani, Lili
    Heliövaara, Markku
    Vartiainen, Erkki
    Räikkönen, Katri
    Masciullo, Corrado
    Starr, John M
    Hicks, Andrew A
    Esposito, Laura
    Kolčić, Ivana
    Farrington, Susan M
    Oostra, Ben
    Zemunik, Tatijana
    Campbell, Harry
    Kirin, Mirna
    Pehlic, Marina
    Faletra, Flavio
    Porteous, David
    Pistis, Giorgio
    Widén, Elisabeth
    Salomaa, Veikko
    Koskinen, Seppo
    Fischer, Krista
    Lehtimäki, Terho
    Heath, Andrew
    McCarthy, Mark I
    Rivadeneira, Fernando
    Montgomery, Grant W
    Tiemeier, Henning
    Hartikainen, Anna-Liisa
    Madden, Pamela A F
    d'Adamo, Pio
    Hastie, Nicholas D
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wright, Alan F
    van Duijn, Cornelia M
    Dunlop, Malcolm
    Rudan, Igor
    Gasparini, Paolo
    Pramstaller, Peter P
    Deary, Ian J
    Toniolo, Daniela
    Eriksson, Johan G
    Jula, Antti
    Raitakari, Olli T
    Metspalu, Andres
    Perola, Markus
    Järvelin, Marjo-Riitta
    Uitterlinden, André
    Visscher, Peter M
    Wilson, James F
    Evidence of Inbreeding Depression on Human Height2012Inngår i: PLOS Genetics, ISSN 1553-7404, Vol. 8, nr 7, s. e1002655-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Stature is a classical and highly heritable complex trait, with 80%–90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ2 = 83.89, df = 1; p = 5.2×10−20). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.

  • 141.
    Moberg, M
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gustavsson, I
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Wilander, E
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gyllensten, U
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    High viral loads of human papillomavirus predict risk of invasive cervical carcinoma.2005Inngår i: Br J Cancer, ISSN 0007-0920, Vol. 92, nr 5, s. 891-4Artikkel i tidsskrift (Fagfellevurdert)
  • 142.
    Moberg, Martin
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gustavsson, Inger
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Real-time PCR-based system for simultaneous quantification of human papillomavirus types associated with high risk of cervical cancer2003Inngår i: J Clin Microbiol, Vol. 41, s. 3221-Artikkel i tidsskrift (Fagfellevurdert)
  • 143.
    Moberg, Martin
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gustavsson, Inger
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Type-specific associations of human papillomavirus load with risk of developing cervical carcinoma in situ.2004Inngår i: Int J Cancer, ISSN 0020-7136, Vol. 112, nr 5, s. 854-9Artikkel i tidsskrift (Fagfellevurdert)
  • 144.
    Mohammad, Faizaan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pandey, Gaurav Kumar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mondal, Tanmoy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Redrup, Lisa
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kanduri, Chandrasekhar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Long noncoding RNA-mediated maintenance of DNA methylation and transcriptional gene silencing2012Inngår i: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 139, nr 15, s. 2792-2803Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Establishment of silencing by noncoding RNAs (ncRNAs) via targeting of chromatin remodelers is relatively well investigated; however, their role in the maintenance of silencing is poorly understood. Here, we explored the functional role of the long ncRNA Kcnq1ot1 in the maintenance of transcriptional gene silencing in the one mega-base Kcnq1 imprinted domain in a transgenic mouse model. By conditionally deleting the Kcnq1ot1 ncRNA at different stages of mouse development, we suggest that Kcnq1ot1 ncRNA is required for the maintenance of the silencing of ubiquitously imprinted genes (UIGs) at all developmental stages. In addition, Kcnq1ot1 ncRNA is also involved in guiding and maintaining the CpG methylation at somatic differentially methylated regions flanking the UIGs, which is a hitherto unknown role for a long ncRNA. On the other hand, silencing of some of the placental-specific imprinted genes (PIGs) is maintained independently of Kcnq1ot1 ncRNA. Interestingly, the non-imprinted genes (NIGs) that escape RNA-mediated silencing are enriched with enhancer-specific modifications. Taken together, this study illustrates the gene-specific maintenance mechanisms operational at the Kcnq1 locus for tissue-specific transcriptional gene silencing and activation.

  • 145. Mondal, Tanmoy
    et al.
    Subhash, Santhilal
    Vaid, Roshan
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Uday, Sireesha
    Reinius, Björn
    Mitra, Sanhita
    Mohammed, Arif
    James, Alva Rani
    Hoberg, Emily
    Moustakas, Aristidis
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Jones, Steven J M
    Gustafsson, Claes M
    Sims, Andrew H
    Westerlund, Fredrik
    Gorab, Eduardo
    Kanduri, Chandrasekhar
    MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA-DNA triplex structures2015Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, artikkel-id 7743Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Long noncoding RNAs (lncRNAs) regulate gene expression by association with chromatin, but how they target chromatin remains poorly understood. We have used chromatin RNA immunoprecipitation-coupled high-throughput sequencing to identify 276 lncRNAs enriched in repressive chromatin from breast cancer cells. Using one of the chromatin-interacting lncRNAs, MEG3, we explore the mechanisms by which lncRNAs target chromatin. Here we show that MEG3 and EZH2 share common target genes, including the TGF-β pathway genes. Genome-wide mapping of MEG3 binding sites reveals that MEG3 modulates the activity of TGF-β genes by binding to distal regulatory elements. MEG3 binding sites have GA-rich sequences, which guide MEG3 to the chromatin through RNA-DNA triplex formation. We have found that RNA-DNA triplex structures are widespread and are present over the MEG3 binding sites associated with the TGF-β pathway genes. Our findings suggest that RNA-DNA triplex formation could be a general characteristic of target gene recognition by the chromatin-interacting lncRNAs.

  • 146.
    Nyström, Niklas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Berg, Tove
    Lundin, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Skog, Oskar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Hansson, Inga
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Frisk, Gun
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Juko-Pecirep, Ivana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Nilsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Finkel, Yigael
    Fuxe, Jonas
    Wanders, Alkwin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Human enterovirus species B in ileocecal Crohn's disease2013Inngår i: Clinical and Translational Gastroenterology, ISSN 2155-384X, E-ISSN 2155-384X, Vol. 4, artikkel-id e38Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES:

    Advanced ileocecal Crohn's disease (ICD) is characterized by strictures, inflammation in the enteric nervous system (myenteric plexitis), and a high frequency of NOD2 mutations. Recent findings implicate a role of NOD2 and another CD susceptibility gene, ATG16L1, in the host response against single-stranded RNA (ssRNA) viruses. However, the role of viruses in CD is unknown. We hypothesized that human enterovirus species B (HEV-B), which are ssRNA viruses with dual tropism both for the intestinal epithelium and the nervous system, could play a role in ICD.

    METHODS:

    We used immunohistochemistry and in situ hybridization to study the general presence of HEV-B and the presence of the two HEV-B subspecies, Coxsackie B virus (CBV) and Echovirus, in ileocecal resections from 9 children with advanced, stricturing ICD and 6 patients with volvulus, and in intestinal biopsies from 15 CD patients at the time of diagnosis.

    RESULTS:

    All patients with ICD had disease-associated polymorphisms in NOD2 or ATG16L1. Positive staining for HEV-B was detected both in the mucosa and in myenteric nerve ganglia in all ICD patients, but in none of the volvulus patients. Expression of the cellular receptor for CBV, CAR, was detected in nerve cell ganglia.

    CONCLUSIONS:

    The common presence of HEV-B in the mucosa and enteric nervous system of ICD patients in this small cohort is a novel finding that warrants further investigation to analyze whether HEV-B has a role in disease onset or progress. The presence of CAR in myenteric nerve cell ganglia provides a possible route of entry for CBV into the enteric nervous system.

  • 147. Ostensson, Ellinor
    et al.
    Hellstrom, Ann-Cathrin
    Hellman, Kristina
    Gustavsson, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Wilander, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Zethraeus, Niklas
    Andersson, Sonia
    Projected cost-effectiveness of repeat high-risk human papillomavirus testing using self-collected vaginal samples in the Swedish cervical cancer screening program2013Inngår i: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 92, nr 7, s. 830-840Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Human papillomavirus (HPV) testing is not currently used in primary cervical cancer screening in Sweden, and corresponding cost-effectiveness is unclear. Objective From a societal perspective, to evaluate the cost-effectiveness of high-risk (HR)-HPV testing using self-collected vaginal samples. Design A cost-effectiveness analysis. Setting The Swedish organized cervical cancer screening program. Methods We constructed a model to simulate the natural history of cervical cancer using Swedish data on cervical cancer risk. For the base-case analysis we evaluated two screening strategies with different screening intervals: (i) cytology screening throughout the woman's lifetime (i.e. conventional cytology strategy) and (ii) conventional cytology screening until age 35years, followed by HR-HPV testing using self-collected vaginal samples in women aged 35years (i.e. combination strategy). Sensitivity analyses were performed, varying model parameters over a significant range of values to identify cost-effective screening strategies. Main outcome measures Average lifetime cost, discounted and undiscounted life-years gained, reduction in cervical cancer risk, incremental cost-effectiveness ratios with and without the cost of added life-years. Results Depending on screening interval, the incremental cost-effectiveness ratios for the combination strategy ranged from Euro43000 to Euro180000 per life-years gained without the cost of added life-years, and from Euro74000 to Euro206000 with costs of added life-years included. Conclusion The combination strategy with a 5-year screening interval is potentially cost-effective compared with no screening, and with current screening practice when using a threshold value of Euro80000 per life-years gained.

  • 148.
    Pan, Gang
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Ameur, Adam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Bysani, Madhusudhan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Lund Univ, Ctr Diabet, Dept Clin Sci, Malmo, Sweden..
    Nord, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Galderma, Uppsala, Sweden..
    Cavalli, Marco
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Essand, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Wadelius, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    PATZ1 down-regulates FADS1 by binding to rs174557 and is opposed by SP1/SREBP1c2017Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, nr 5, s. 2408-2422Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The FADS1 and FADS2 genes in the FADS cluster encode the rate-limiting enzymes in the synthesis of long-chain polyunsaturated fatty acids (LC-PUFAs). Genetic variation in this region has been associated with a large number of diseases and traits many of them correlated to differences in metabolism of PUFAs. However, the causative variants leading to these associations have not been identified. Here we find that the multiallelic rs174557 located in an AluYe5 element in intron 1 of FADS1 is functional and lies within a PATZ1 binding site. The derived allele of rs174557, which is the common variant in most populations, diminishes binding of PATZ1, a transcription factor conferring allele-specific downregulation of FADS1 The PATZ1 binding site overlaps with a SP1 site. The competitive binding between the suppressive PATZ1 and the activating complex of SP1 and SREBP1c determines the enhancer activity of this region, which regulates expression of FADS1.

  • 149. Parsa, Afshin
    et al.
    Fuchsberger, Christian
    Koettgen, Anna
    O'Seaghdha, Conall M.
    Pattaro, Cristian
    de Andrade, Mariza
    Chasman, Daniel I.
    Teumer, Alexander
    Endlich, Karlhans
    Olden, Matthias
    Chen, Ming-Huei
    Tin, Adrienne
    Kim, Young J.
    Taliun, Daniel
    Li, Man
    Feitosa, Mary
    Gorski, Mathias
    Yang, Qiong
    Hundertmark, Claudia
    Foster, Meredith C.
    Glazer, Nicole
    Isaacs, Aaron
    Rao, Madhumathi
    Smith, Albert V.
    O'Connell, Jeffrey R.
    Struchalin, Maksim
    Tanaka, Toshiko
    Li, Guo
    Hwang, Shih-Jen
    Atkinson, Elizabeth J.
    Lohman, Kurt
    Cornelis, Marilyn C.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Toenjes, Anke
    Dehghan, Abbas
    Couraki, Vincent
    Holliday, Elizabeth G.
    Sorice, Rossella
    Kutalik, Zoltan
    Lehtimaeki, Terho
    Esko, Tonu
    Deshmukh, Harshal
    Ulivi, Sheila
    Chu, Audrey Y.
    Murgia, Federico
    Trompet, Stella
    Imboden, Medea
    Kollerits, Barbara
    Pistis, Giorgio
    Harris, Tamara B.
    Launer, Lenore J.
    Aspelund, Thor
    Eiriksdottir, Gudny
    Mitchell, Braxton D.
    Boerwinkle, Eric
    Schmidt, Helena
    Hofer, Edith
    Hu, Frank
    Demirkan, Ayse
    Oostra, Ben A.
    Turner, Stephen T.
    Ding, Jingzhong
    Andrews, Jeanette S.
    Freedman, Barry I.
    Giulianini, Franco
    Koenig, Wolfgang
    Illig, Thomas
    Doering, Angela
    Wichmann, H. -Erich
    Zgaga, Lina
    Zemunik, Tatijana
    Boban, Mladen
    Minelli, Cosetta
    Wheeler, Heather E.
    Igl, Wilmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Zaboli, Ghazal
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Wild, Sarah H.
    Wright, Alan F.
    Campbell, Harry
    Ellinghaus, David
    Noethlings, Ute
    Jacobs, Gunnar
    Biffar, Reiner
    Ernst, Florian
    Homuth, Georg
    Kroemer, Heyo K.
    Nauck, Matthias
    Stracke, Sylvia
    Voelker, Uwe
    Voelzke, Henry
    Kovacs, Peter
    Stumvoll, Michael
    Maegi, Reedik
    Hofman, Albert
    Uitterlinden, Andre G.
    Rivadeneira, Fernando
    Aulchenko, Yurii S.
    Polasek, Ozren
    Hastie, Nick
    Vitart, Veronique
    Helmer, Catherine
    Wang, Jie Jin
    Stengel, Benedicte
    Ruggiero, Daniela
    Bergmann, Sven
    Kaehoenen, Mika
    Viikari, Jorma
    Nikopensius, Tiit
    Province, Michael
    Colhoun, Helen
    Doney, Alex
    Robino, Antonietta
    Kraemer, Bernhard K.
    Portas, Laura
    Ford, Ian
    Buckley, Brendan M.
    Adam, Martin
    Thun, Gian-Andri
    Paulweber, Bernhard
    Haun, Margot
    Sala, Cinzia
    Mitchell, Paul
    Ciullo, Marina
    Vollenweider, Peter
    Raitakari, Olli
    Metspalu, Andres
    Palmer, Colin
    Gasparini, Paolo
    Pirastu, Mario
    Jukema, J. Wouter
    Probst-Hensch, Nicole M.
    Kronenberg, Florian
    Toniolo, Daniela
    Gudnason, Vilmundur
    Shuldiner, Alan R.
    Coresh, Josef
    Schmidt, Reinhold
    Ferrucci, Luigi
    Van Duijn, Cornelia M.
    Borecki, Ingrid
    Kardia, Sharon L. R.
    Liu, Yongmei
    Curhan, Gary C.
    Rudan, Igor
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Wilson, James F.
    Franke, Andre
    Pramstaller, Peter P.
    Rettig, Rainer
    Prokopenko, Inga
    Witteman, Jacqueline
    Hayward, Caroline
    Ridker, Paul M.
    Bochud, Murielle
    Heid, Iris M.
    Siscovick, David S.
    Fox, Caroline S.
    Kao, W. Linda
    Boeger, Carsten A.
    Common Variants in Mendelian Kidney Disease Genes and Their Association with Renal Function2013Inngår i: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 24, nr 12, s. 2105-2117Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

  • 150. Pattaro, Cristian
    et al.
    Aulchenko, Yurii S.
    Isaacs, Aaron
    Vitart, Veronique
    Hayward, Caroline
    Franklin, Christopher S.
    Polasek, Ozren
    Kolcic, Ivana
    Biloglav, Zrinka
    Campbell, Susan
    Hastie, Nick
    Lauc, Gordan
    Meitinger, Thomas
    Oostra, Ben A.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Wilson, James F.
    Pichler, Irene
    Hicks, Andrew A.
    Campbell, Harry
    Wright, Alan F.
    Rudan, Igor
    van Duijn, Cornelia M.
    Riegler, Peter
    Marroni, Fabio
    Pramstaller, Peter P.
    Genome-wide linkage analysis of serum creatinine in three isolated European populations2009Inngår i: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 76, nr 3, s. 297-306Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There is increasing evidence for a role of genetic predisposition in the etiology of kidney disease, but linkage scans have been poorly replicated. Here we performed a genome-wide linkage analysis of serum creatinine on 2859 individuals from isolated villages in South Tyrol (Italy), Rucphen (The Netherlands) and Vis Island (Croatia), populations that have been stable and permanently resident in their region. Linkage of serum creatinine levels to loci on chromosomes 7p14, 9p21, 11p15, 15q15-21, 16p13, and 18p11 was successfully replicated in at least one discovery population or in the pooled analysis. A novel locus was found on chromosome 10p11. Linkage to chromosome 22q13, independent of diabetes and hypertension, was detected over a region containing the non-muscle myosin heavy chain type II isoform A (MYH9) gene (LOD score=3.52). In non-diabetic individuals, serum creatinine was associated with this gene in two of the three populations and in meta-analysis (SNP rs11089788, P-value=0.0089). In populations sharing a homogeneous environment and genetic background, heritability of serum creatinine was higher than in outbred populations, with consequent detection of a larger number of loci than reported before. Our finding of a replicated association of serum creatinine with the MYH9 gene, recently linked to pathological renal conditions in African Americans, suggests that this gene may also influence kidney function in healthy Europeans.

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