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Nature Research, Nature Genetics, 2(49), p. 186-192, 2017

DOI: 10.1038/ng.3761

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Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7

Journal article published in 2017 by Yang Luo, Katrina M. de Lange, Luke Jostins, Loukas Moutsianas, Joshua Randall, Nicholas A. Kennedy, Christopher A. Lamb, Shane McCarthy ORCID, Tariq Ahmad, Cathryn Edwards ORCID, Eva Goncalves Serra, Ailsa Hart, Chris Hawkey, John C. Mansfield, Craig Mowat and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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.