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Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.

ABSTRACT: Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

SUBMITTER: Anderson CA

PROVIDER: S-EPMC3084597 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.

Anderson Carl A CA Boucher Gabrielle G Lees Charlie W CW Franke Andre A D'Amato Mauro M Taylor Kent D KD Lee James C JC Goyette Philippe P Imielinski Marcin M Latiano Anna A Lagacé Caroline C Scott Regan R Amininejad Leila L Bumpstead Suzannah S Baidoo Leonard L Baldassano Robert N RN Barclay Murray M Bayless Theodore M TM Brand Stephan S Büning Carsten C Colombel Jean-Frédéric JF Denson Lee A LA De Vos Martine M Dubinsky Marla M Edwards Cathryn C Ellinghaus David D Fehrmann Rudolf S N RS Floyd James A B JA Florin Timothy T Franchimont Denis D Franke Lude L Georges Michel M Glas Jürgen J Glazer Nicole L NL Guthery Stephen L SL Haritunians Talin T Hayward Nicholas K NK Hugot Jean-Pierre JP Jobin Gilles G Laukens Debby D Lawrance Ian I Lémann Marc M Levine Arie A Libioulle Cecile C Louis Edouard E McGovern Dermot P DP Milla Monica M Montgomery Grant W GW Morley Katherine I KI Mowat Craig C Ng Aylwin A Newman William W Ophoff Roel A RA Papi Laura L Palmieri Orazio O Peyrin-Biroulet Laurent L Panés Julián J Phillips Anne A Prescott Natalie J NJ Proctor Deborah D DD Roberts Rebecca R Russell Richard R Rutgeerts Paul P Sanderson Jeremy J Sans Miquel M Schumm Philip P Seibold Frank F Sharma Yashoda Y Simms Lisa A LA Seielstad Mark M Steinhart A Hillary AH Targan Stephan R SR van den Berg Leonard H LH Vatn Morten M Verspaget Hein H Walters Thomas T Wijmenga Cisca C Wilson David C DC Westra Harm-Jan HJ Xavier Ramnik J RJ Zhao Zhen Z ZZ Ponsioen Cyriel Y CY Andersen Vibeke V Torkvist Leif L Gazouli Maria M Anagnou Nicholas P NP Karlsen Tom H TH Kupcinskas Limas L Sventoraityte Jurgita J Mansfield John C JC Kugathasan Subra S Silverberg Mark S MS Halfvarson Jonas J Rotter Jerome I JI Mathew Christopher G CG Griffiths Anne M AM Gearry Richard R Ahmad Tariq T Brant Steven R SR Chamaillard Mathias M Satsangi Jack J Cho Judy H JH Schreiber Stefan S Daly Mark J MJ Barrett Jeffrey C JC Parkes Miles M Annese Vito V Hakonarson Hakon H Radford-Smith Graham G Duerr Richard H RH Vermeire Séverine S Weersma Rinse K RK Rioux John D JD

Nature genetics 20110206 3

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions u ...[more]

PMID: 21297633

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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.

Dataset Information

Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.

Publications

Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.

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