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Genome-wide association identifies multiple ulcerative colitis susceptibility loci.

ABSTRACT: Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.

SUBMITTER: McGovern DP

PROVIDER: S-EPMC3087600 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Genome-wide association identifies multiple ulcerative colitis susceptibility loci.

McGovern Dermot P B DP Gardet Agnès A Törkvist Leif L Goyette Philippe P Essers Jonah J Taylor Kent D KD Neale Benjamin M BM Ong Rick T H RT Lagacé Caroline C Li Chun C Green Todd T Stevens Christine R CR Beauchamp Claudine C Fleshner Phillip R PR Carlson Marie M D'Amato Mauro M Halfvarson Jonas J Hibberd Martin L ML Lördal Mikael M Padyukov Leonid L Andriulli Angelo A Colombo Elisabetta E Latiano Anna A Palmieri Orazio O Bernard Edmond-Jean EJ Deslandres Colette C Hommes Daan W DW de Jong Dirk J DJ Stokkers Pieter C PC Weersma Rinse K RK Sharma Yashoda Y Silverberg Mark S MS Cho Judy H JH Wu Jing J Roeder Kathryn K Brant Steven R SR Schumm L Phillip LP Duerr Richard H RH Dubinsky Marla C MC Glazer Nicole L NL Haritunians Talin T Ippoliti Andy A Melmed Gil Y GY Siscovick David S DS Vasiliauskas Eric A EA Targan Stephan R SR Annese Vito V Wijmenga Cisca C Pettersson Sven S Rotter Jerome I JI Xavier Ramnik J RJ Daly Mark J MJ Rioux John D JD Seielstad Mark M

Nature genetics 20100314 4

Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci ...[more]

PMID: 20228799

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Project description:BackgroundUlcerative colitis (UC), a complex polygenic disorder, is one of the main subphenotypes of inflammatory bowel disease. A comprehensive dissection of the genetic etiology of UC needs to assess the contribution of rare genetic variants including copy number variations (CNVs) to disease risk. In this study, we performed a multi-step genome-wide case-control analysis to interrogate the presence of disease-relevant rare copy number variants.MethodsOne thousand one hundred twenty-one German UC patients and 1770 healthy controls were initially screened for rare deletions and duplications employing SNP-array data. Quantitative PCR and high density custom array-CGH were used for validation of identified CNVs and fine mapping. Two main follow-up panels consisted of an independent cohort of 451 cases and 1274 controls, in which CNVs were assayed through quantitative PCR, and a British cohort of 2396 cases versus 4886 controls with CNV genotypes based on array data. Additional sample sets were assessed for targeted and in silico replication.ResultsTwenty-four rare copy number variants (14 deletions and 10 duplications), overrepresented in UC patients were identified in the initial screening panel. Follow-up of these CNV regions in four independent case-control series as well as an additional public in silico control group (totaling 4439 UC patients and 15,961 healthy controls) revealed three copy number variants enriched in UC patients; a 15.8 kb deletion upstream of ABCC4 and CLDN10 at13q32.1 (0.43% cases, 0.11% controls), a 119 kb duplication at 7p22.1, overlapping RNF216, ZNF815, OCM and CCZ1 (0.13% cases, 0.01% controls) and a 134 kb large duplication upstream of the KCNK9 gene at 8q24.3 (0.22% carriers among cases, 0.03% carriers among controls). The trend of association with UC was present after the P-values were corrected for combining data from different subpopulations. Break-point mapping of the deleted region suggested non-allelic homologous recombination as the mechanism underlying its formation.ConclusionOur study presents a pragmatic approach for effective rare CNV screening of SNP-array data sets and implicates the potential contribution of rare structural variants in the pathogenesis of UC.

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Genome-wide association identifies multiple ulcerative colitis susceptibility loci.

Publications

Genome-wide association identifies multiple ulcerative colitis susceptibility loci.

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