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      Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci

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          Abstract

          Alopecia areata (AA) is a prevalent autoimmune disease with ten known susceptibility loci. Here we perform the first meta-analysis in AA by combining data from two genome-wide association studies (GWAS), and replication with supplemented ImmunoChip data for a total of 3,253 cases and 7,543 controls. The strongest region of association is the MHC, where we fine-map 4 independent effects, all implicating HLA-DR as a key etiologic driver. Outside the MHC, we identify two novel loci that exceed statistical significance, containing ACOXL/BCL2L11(BIM) (2q13); GARP (LRRC32) (11q13.5), as well as a third nominally significant region SH2B3(LNK)/ATXN2 (12q24.12). Candidate susceptibility gene expression analysis in these regions demonstrates expression in relevant immune cells and the hair follicle. We integrate our results with data from seven other autoimmune diseases and provide insight into the alignment of AA within these disorders. Our findings uncover new molecular pathways disrupted in AA, including autophagy/apoptosis, TGFß/Tregs and JAK kinase signaling, and support the causal role of aberrant immune processes in AA.

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          Most cited references35

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          A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer.

          We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 SNPs in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls. We identified four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer and confirmed this association in 1,776 affected individuals and 2,072 controls from three additional studies. Across the four studies, the association with all four SNPs was highly statistically significant (P(trend) for the most strongly associated SNP (rs1219648) = 1.1 x 10(-10); population attributable risk = 16%). Four SNPs at other loci most strongly associated with breast cancer in the initial GWAS were not associated in the replication studies. Our summary results from the GWAS are available online in a form that should speed the identification of additional risk loci.
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            Genome-wide association study of prostate cancer identifies a second risk locus at 8q24.

            Recently, common variants on human chromosome 8q24 were found to be associated with prostate cancer risk. While conducting a genome-wide association study in the Cancer Genetic Markers of Susceptibility project with 550,000 SNPs in a nested case-control study (1,172 cases and 1,157 controls of European origin), we identified a new association at 8q24 with an independent effect on prostate cancer susceptibility. The most significant signal is 70 kb centromeric to the previously reported SNP, rs1447295, but shows little evidence of linkage disequilibrium with it. A combined analysis with four additional studies (total: 4,296 cases and 4,299 controls) confirms association with prostate cancer for rs6983267 in the centromeric locus (P = 9.42 x 10(-13); heterozygote odds ratio (OR): 1.26, 95% confidence interval (c.i.): 1.13-1.41; homozygote OR: 1.58, 95% c.i.: 1.40-1.78). Each SNP remained significant in a joint analysis after adjusting for the other (rs1447295 P = 1.41 x 10(-11); rs6983267 P = 6.62 x 10(-10)). These observations, combined with compelling evidence for a recombination hotspot between the two markers, indicate the presence of at least two independent loci within 8q24 that contribute to prostate cancer in men of European ancestry. We estimate that the population attributable risk of the new locus, marked by rs6983267, is higher than the locus marked by rs1447295 (21% versus 9%).
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              TRAF1-C5 as a risk locus for rheumatoid arthritis--a genomewide study.

              Rheumatoid arthritis has a complex mode of inheritance. Although HLA-DRB1 and PTPN22 are well-established susceptibility loci, other genes that confer a modest level of risk have been identified recently. We carried out a genomewide association analysis to identify additional genetic loci associated with an increased risk of rheumatoid arthritis. We genotyped 317,503 single-nucleotide polymorphisms (SNPs) in a combined case-control study of 1522 case subjects with rheumatoid arthritis and 1850 matched control subjects. The patients were seropositive for autoantibodies against cyclic citrullinated peptide (CCP). We obtained samples from two data sets, the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA). Results from NARAC and EIRA for 297,086 SNPs that passed quality-control filters were combined with the use of Cochran-Mantel-Haenszel stratified analysis. SNPs showing a significant association with disease (P<1x10(-8)) were genotyped in an independent set of case subjects with anti-CCP-positive rheumatoid arthritis (485 from NARAC and 512 from EIRA) and in control subjects (1282 from NARAC and 495 from EIRA). We observed associations between disease and variants in the major-histocompatibility-complex locus, in PTPN22, and in a SNP (rs3761847) on chromosome 9 for all samples tested, the latter with an odds ratio of 1.32 (95% confidence interval, 1.23 to 1.42; P=4x10(-14)). The SNP is in linkage disequilibrium with two genes relevant to chronic inflammation: TRAF1 (encoding tumor necrosis factor receptor-associated factor 1) and C5 (encoding complement component 5). A common genetic variant at the TRAF1-C5 locus on chromosome 9 is associated with an increased risk of anti-CCP-positive rheumatoid arthritis. Copyright 2007 Massachusetts Medical Society.
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                Author and article information

                Journal
                101528555
                37539
                Nat Commun
                Nat Commun
                Nature communications
                2041-1723
                21 January 2015
                22 January 2015
                2015
                22 July 2015
                : 6
                : 5966
                Affiliations
                [1 ]Institute of Human Genetics, University of Bonn, Bonn, Germany
                [2 ]Department of Dermatology, Columbia University, NY, NY
                [3 ]Department of Epidemiology, Columbia University, NY, NY
                [4 ]Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA
                [5 ]Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA
                [6 ]Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
                [7 ]German Center for Neurodegenerative Diseases, Bonn, Germany
                [8 ]Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn
                [9 ]Department of Genomics, Life&Brain Center, University Bonn, Bonn, Germany
                [10 ]Department of Dermatology, MD Anderson Cancer Center, Houston,TX
                [11 ]Department of Dermatology, University of Minnesota, Minneapolis, MN
                [12 ]Department of Dermatology, University of Colorado, Denver, CO, US
                [13 ]Department of Dermatology, University of California, San Francisco, San Francisco CA
                [14 ]Department of Genetics & Development, Columbia University, NY, NY
                [15 ]Institute of Medical Informatics, Biometry, and Epidemiology, University Duisburg-Essen, Essen, Germany
                [16 ]Department of Dermatology, University of Münster, Münster, Germany
                [17 ]Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Berlin, Germany
                [18 ]Department of Dermatology, University of Munich, Munich, Germany
                [19 ]Dermatological Practice, Hair and Nail, Wesseling, Germany
                [20 ]Dermatological Practice, Paderborn, Germany
                [21 ]Community and Family Medicine and Genetics, Dartmouth College, Hanover, NH, US
                [22 ]The Feinstein Institute for Medical Research, Manhasset NY
                [23 ]Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
                [24 ]Department of Medicine Columbia University, NY, NY
                [25 ]Department of Epidemiology, University Medical Center Utrecht, Utrecht, The Netherlands.
                Author notes
                Address for correspondence Angela M. Christiano, Ph.D. Columbia University College of Physicians & Surgeons Russ Berrie Medical Science Pavilion 1150 St. Nicholas Avenue, Room 303B New York, NY 10032 amc65@ 123456columbia.edu
                Article
                NIHMS645117
                10.1038/ncomms6966
                4451186
                25608926
                b23d6a54-6425-484d-a10f-2ea42db5e801
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