@article {Luo058347, author = {Yang Luo and Katrina M. de Lange and Luke Jostins and Loukas Moutsianas and Joshua Randall and Nicholas A. Kennedy and Christopher A. Lamb and Shane McCarthy and Tariq Ahmad and Cathryn Edwards and Eva Goncalves Serra and Ailsa Hart and Chris Hawkey and John C. Mansfield and Craig Mowat and William G. Newman and Sam Nichols and Martin Pollard and Jack Satsangi and Alison Simmons and Mark Tremelling and Holm Uhlig and David C. Wilson and James C. Lee and Natalie J. Prescott and Charlie W. Lees and Christopher G. Mathew and Miles Parkes and Jeffrey C. Barrett and Carl A. Anderson}, title = {Exploring the genetic architecture of inflammatory bowel disease by whole genome sequencing identifies association at ADCY7}, elocation-id = {058347}, year = {2016}, doi = {10.1101/058347}, publisher = {Cold Spring Harbor Laboratory}, abstract = {In order to further resolve the genetic architecture of the inflammatory bowel diseases, ulcerative colitis and Crohn{\textquoteright}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{\textquoteright}s disease risk genes, suggesting that more comprehensive sequencing studies will continue to improve our understanding of the biology of complex diseases.}, URL = {https://www.biorxiv.org/content/early/2016/06/11/058347}, eprint = {https://www.biorxiv.org/content/early/2016/06/11/058347.full.pdf}, journal = {bioRxiv} }