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 scan1, 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 × 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 × 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.
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This study was supported in part by US National Center for Research Resources (NCRR) grant M01-RR00425 to the Cedars-Sinai General Research Center Genotyping core; US National Institutes of Health/NIDDK grant P01-DK046763; Diabetes Endocrinology Research Center grant DK063491; Cedars-Sinai Medical Center Inflammatory Bowel Disease Research Funds. Additional funding was provided by grants DK76984 (M.C.D.) and DK084554 (M.C.D. and D.P.B.M.). Cardiovascular Health Study research reported in this article was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150 and N01-HC-45133; grant numbers U01 HL080295 and R01 HL087652 from the US National Heart, Lung, and Blood Institute; and additional contribution from the US National Institute of Neurological Disorders and Stroke. A full list of principal Cardiovascular Health Study investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. A.G. is supported by the Crohn's and Colitis Foundation of America. R.J.X. and M.J.D. are supported by grants DK83756, DK086502 and DK043351 (NIDDK).
The NIDDK IBD Genetics Consortium is funded by the following grants: DK062431 (S.R.B.), DK062422 (J.H.C.), DK062420 (R.H.D.), DK062432 (J.D.R.), DK062423 (M.S.S.), DK062413 (D.P.B.M.) and DK062429 (J.H.C.). J.H.C. is also funded by Bohmfalk Funds for Medical Research, Burroughs Wellcome Medical Foundation and the Crohn's and Colitis Foundation of America. J.D.R. is also funded by grants from the US National Institute of Allergy and Infectious Diseases (AI065687; AI067152) and from the US National Institute of Diabetes and Digestive and Kidney Diseases (DK064869).
Activities in Sweden were supported by the Swedish Society of Medicine, the Bengt Ihre Foundation, the Karolinska Institutet, the Swedish National Program for IBD Genetics, the Swedish Organization for IBD, the Swedish Medical Research Council, the Soderbergh Foundation and the Swedish Cancer Foundation. Support for genotyping and genetic data analysis was provided by the Singapore National Cancer Centre, Singapore General Hospital and the Singapore Millennium Foundation (to S.P.) and the Agency for Science Technology and Research (A*STAR), Singapore (to M.L.H. and M.S.). Genotyping and DNA handling at the Genome Institute of Singapore were performed by W.Y. Meah, K.K. Heng, H.B. Toh, X. Lin, S. Rajaram, D. Tan and C.H. Wong. We are grateful to the funders and investigators of the Epidemiological Investigation of Rheumatoid Arthritis for providing genotype data from healthy Swedish individuals.
Supplementary Tables 1–5 and Supplementary Figures 1 and 2