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

Lookup NU author(s): Dr Chris LambORCiD, Dr John Mansfield

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Nature Publishing Group, 2017.

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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 similar to 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.


Publication metadata

Author(s): Luo Y, de Lange KM, Jostins L, Moutsianas L, Randall J, Kennedy NA, Lamb CA, McCarthy S, Ahmad T, Edwards C, Serra EG, Hart A, Hawkey C, Mansfield JC, Mowat C, Newman WG, Nichols S, Pollard M, Satsangi J, Simmons A, Tremelling M, Uhlig H, Wilson DC, Lee JC, Prescott NJ, Lees CW, Mathew CG, Parkes M, Barrett JC, Anderson CA

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2017

Volume: 49

Issue: 2

Pages: 186-192

Print publication date: 01/02/2017

Online publication date: 09/01/2017

Acceptance date: 07/12/2016

Date deposited: 09/01/2019

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/ng.3761

DOI: 10.1038/ng.3761


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Funding

Funder referenceFunder name
Crohn's and Colitis Foundation of America (CCFA)
Economic and Social Research Council
Leona M. and Harry B. Helmsley Charitable Trust
UK Department of Health via NIHR comprehensive Biomedical Research Centre awards
Woolf Fisher Trust scholarship
BRC
Crohn's and Colitis UK
NIHR
NIHR Newcastle Biomedical Research Centre
098051Wellcome Trust
093885/Z/10/ZWellcome Trust
MR/J00314X/1Medical Research Council, UK

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