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Genome-wide Association Study in a High-Risk Isolate for Multiple Sclerosis Reveals Associated Variants in STAT3 Gene |
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| Authors: | Eveliina Jakkula Virpi Leppä Anna-Maija Sulonen Teppo Varilo Suvi Kallio Anu Kemppinen Shaun Purcell Keijo Koivisto Marja-Liisa Sumelahti Tuula Pirttilä Arpo Aromaa Helle Bach Søndergaard Inger-Lise Mero Stacey B Gabriel Stephen L Hauser Chris Polman David A Hafler Mark J Daly Aarno Palotie Janna Saarela Leena Peltonen |
| Institution: | 1 Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00290, Finland 2 Helsinki Biomedical Graduate School, University of Helsinki, Helsinki 00290, Finland 3 Department of Medical Genetics, University of Helsinki, Helsinki 00290, Finland 4 Department of Neurology, Neuroscience Programme, Biomedicum Helsinki, University of Helsinki, Helsinki 00290, Finland 5 Unit of Public Health Genomics, National Institute for Health and Welfare, Helsinki 00271, Finland 6 Unit of Living Conditions, Health and Wellbeing, National Institute for Health and Welfare, Helsinki 00271, Finland 7 Program in Medical and Population Genetics and Genetic Analysis Platform, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA 8 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA 9 Central Hospital of Seinäjoki, 60220 Seinäjoki, Finland 10 School of Public Health, University of Tampere, 33014 Tampere, Finland 11 Department of Neurology, Tampere University Hospital, 33521 Tampere, Finland 12 Department of Neurology and Neuroscience, Kuopio University Hospital, 70211 Kuopio, Finland 13 Department of Neurology, Oulu University Hospital, 90014 Oulu, Finland 14 Danish Multiple Sclerosis Research Center, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark 15 Department of Neurology, Oslo University Hospital, Ullevål and University of Oslo, 0407 Oslo, Norway 16 Institute of Immunology, Oslo University Hospital, Rikshospitalet, 0027 Oslo, Norway 17 Department of Neurology, University of California at San Francisco, San Francisco, CA 94143-0248, USA 18 Departments of Neurology, Neuroradiology and Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland 19 Department of Neurology, Vrije Universiteit Medical Centre, 1085 Amsterdam, The Netherlands 20 Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02035, USA 21 Division of Molecular Immunology, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02035, USA 22 Department of Neurology, Yale School of Medicine, New Haven, CT 06520-8018, USA 23 Wellcome Trust Sanger Institute, Hinxton, CB10 1HH Cambridge, UK |
| Abstract: | Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p < 10−4 were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 × 10−10, OR 0.87, confidence interval 0.83–0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits. |
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