PT  - JOURNAL ARTICLE
AU  - Yang Luo
AU  - Katrina M. de Lange
AU  - Luke Jostins
AU  - Loukas Moutsianas
AU  - Joshua Randall
AU  - Nicholas A. Kennedy
AU  - Christopher A. Lamb
AU  - Shane McCarthy
AU  - Tariq Ahmad
AU  - Cathryn Edwards
AU  - Eva Goncalves Serra
AU  - Ailsa Hart
AU  - Chris Hawkey
AU  - John C. Mansfield
AU  - Craig Mowat
AU  - William G. Newman
AU  - Sam Nichols
AU  - Martin Pollard
AU  - Jack Satsangi
AU  - Alison Simmons
AU  - Mark Tremelling
AU  - Holm Uhlig
AU  - David C. Wilson
AU  - James C. Lee
AU  - Natalie J. Prescott
AU  - Charlie W. Lees
AU  - Christopher G. Mathew
AU  - Miles Parkes
AU  - Jeffrey C. Barrett
AU  - Carl A. Anderson
TI  - Exploring the genetic architecture of inflammatory bowel disease by whole genome sequencing identifies association at <em>ADCY7</em>
AID  - 10.1101/058347
DP  - 2016 Jan 01
TA  - bioRxiv
PG  - 058347
4099  - http://biorxiv.org/content/early/2016/06/11/058347.short
4100  - http://biorxiv.org/content/early/2016/06/11/058347.full
AB  - In order 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. To increase power we imputed from these sequences into new and existing GWAS 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 risk of ulcerative colitis, and offers insight into a new aspect of disease biology. Despite good statistical power, we did not identify any other new low-frequency risk variants, and found that such variants as a class explained little heritability. We did detect 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 our understanding of the biology of complex diseases.