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Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region.

ABSTRACT: Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P < 1 x 10(-5) were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 x 10(-17)), 16q22 (CDH1 and CDH3; P = 2.8 x 10(-8)) and 7q31 (LAMB1; P = 3.0 x 10(-8)). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis.

SUBMITTER: UK IBD Genetics Consortium

PROVIDER: S-EPMC2812019 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region.

Barrett Jeffrey C JC Lee James C JC Lees Charles W CW Prescott Natalie J NJ Anderson Carl A CA Phillips Anne A Wesley Emma E Parnell Kirstie K Zhang Hu H Drummond Hazel H Nimmo Elaine R ER Massey Dunecan D Blaszczyk Kasia K Elliott Timothy T Cotterill Lynn L Dallal Helen H Lobo Alan J AJ Mowat Craig C Sanderson Jeremy D JD Jewell Derek P DP Newman William G WG Edwards Cathryn C Ahmad Tariq T Mansfield John C JC Satsangi Jack J Parkes Miles M Mathew Christopher G CG Donnelly Peter P Peltonen Leena L Blackwell Jenefer M JM Bramon Elvira E Brown Matthew A MA Casas Juan P JP Corvin Aiden A Craddock Nicholas N Deloukas Panos P Duncanson Audrey A Jankowski Janusz J Markus Hugh S HS Mathew Christopher G CG McCarthy Mark I MI Palmer Colin N A CN Plomin Robert R Rautanen Anna A Sawcer Stephen J SJ Samani Nilesh N Trembath Richard C RC Viswanathan Anath C AC Wood Nicholas N Spencer Chris C A CC Barrett Jeffrey C JC Bellenguez Céline C Davison Daniel D Freeman Colin C Strange Amy A Donnelly Peter P Langford Cordelia C Hunt Sarah E SE Edkins Sarah S Gwilliam Rhian R Blackburn Hannah H Bumpstead Suzannah J SJ Dronov Serge S Gillman Matthew M Gray Emma E Hammond Naomi N Jayakumar Alagurevathi A McCann Owen T OT Liddle Jennifer J Perez Marc L ML Potter Simon C SC Ravindrarajah Radhi R Ricketts Michelle M Waller Matthew M Weston Paul P Widaa Sara S Whittaker Pamela P Deloukas Panos P Peltonen Leena L Mathew Christopher G CG Blackwell Jenefer M JM Brown Matthew A MA Corvin Aiden A McCarthy Mark I MI Spencer Chris C A CC Attwood Antony P AP Stephens Jonathan J Sambrook Jennifer J Ouwehand Willem H WH McArdle Wendy L WL Ring Susan M SM Strachan David P DP

Nature genetics 20091115 12

Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P < 1 x 10(-5) were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one bio ...[more]

PMID: 19915572

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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

Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region.

Publications

Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region.

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