Nature genetics · 2017
Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7.
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Luo Yang, de Lange Katrina M, Jostins Luke, Moutsianas Loukas, Randall Joshua, Kennedy Nicholas A, Lamb Christopher A, McCarthy Shane, Ahmad Tariq, Edwards Cathryn, Serra Eva Goncalves, Hart Ailsa, Hawkey Chris, Mansfield John C, Mowat Craig, Newman William G, Nichols Sam, Pollard Martin, Satsangi Jack, Simmons Alison, Tremelling Mark, Uhlig Holm, Wilson David C, Lee James C, Prescott Natalie J, Lees Charlie W, Mathew Christopher G, Parkes Miles, Barrett Jeffrey C, Anderson Carl A
Аннотация
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.