Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at $\textit{ADCY7}$

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Luo, Y 
de Lange, KM 
Jostins, L 
Moutsianas, L 
Randall, J 

To further resolve the genetic architecture of the inflammatory bowel diseases ulcerative colitis and Crohn’s disease, we sequenced the whole genomes of 4,280 patients at low coverage and compared them to 3,652 previously sequenced population controls across 73.5 million variants. We then imputed from these sequences into new and existing genome-wide association study cohorts and tested for association at ~12 million variants in a total of 16,432 cases and 18,843 controls. We discovered a 0.6% frequency missense variant in ADCY7 that doubles the risk of ulcerative colitis. Despite good statistical power, we did not identify any other new low-frequency risk variants and found that such variants explained little heritability. We detected a burden of very rare, damaging missense variants in known Crohn’s disease risk genes, suggesting that more comprehensive sequencing studies will continue to improve understanding of the biology of complex diseases.

DNA sequencing, genetic association study, inflammatory bowel disease
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Nature Genetics
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Nature Publishing Group
Medical Research Council (MR/M00533X/1)
National Association for Colitis and Crohn's Disease (NACC) (MR/M00533X/1)
This work was co-funded by the Wellcome Trust (098051) and the Medical Research Council, UK (MR/J00314X/1). Case collections were supported by Crohn’s and Colitis UK. K.M.d.L., L.M., Y.L., C.A.L., C.A.A. and J.C.B. are supported by the Wellcome Trust (098051; 093885/Z/10/Z). K.M.d.L. is supported by a Woolf Fisher Trust scholarship. C.A.L. is a clinical lecturer funded by the NIHR. H.U. is supported by the Crohn’s and Colitis Foundation of America (CCFA) and the Leona M. and Harry B. Helmsley Charitable Trust. We acknowledge support from the UK Department of Health via NIHR comprehensive Biomedical Research Centre awards to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London and to Addenbrooke’s Hospital, Cambridge, in partnership with the University of Cambridge, and the BRC to the Oxford IBD cohort study, University of Oxford. This research was also supported by the NIHR Newcastle Biomedical Research Centre. The UK Household Longitudinal Study is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The survey was conducted by NatCen, and the genome-wide scan data were analyzed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website. We are grateful for genotyping data from the British Society for Surgery of the Hand Genetics of Dupuytren’s Disease consortium and L. Southam for assistance with genotype intensities. This research has been conducted using the UK Biobank Resource.