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Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7
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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.
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“Convergences between rare variants and fine-mapped GWAS signals have been previously observed in other traits e.g.,34,35”
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Metadata
- Authors
- Luo, Y., de Lange, K. M., Jostins, L., Moutsianas, L., Randall, J., Kennedy, N. A., Lamb, C. A., McCarthy, S., Ahmad, T., Edwards, C., Serra, E. G., Hart, A., Hawkey, C., Mansfield, J. C., Mowat, C., Newman, W. G., Nichols, S., Pollard, M., Satsangi, J., Simmons, A., Tremelling, M., Uhlig, H., Wilson, D. C., Lee, J. C., Prescott, N. J., Lees, C. W., Mathew, C. G., Parkes, M., Barrett, J. C., & Anderson, C. A.
- Affiliations
- Broad Institute (US)
- Centre for Human Genetics (GB)
- Wellcome Sanger Institute (GB)
- University of Exeter (GB)
- Newcastle University (GB)
- Torbay Hospital (GB)
- St Mark's Hospital (GB)
- Queen's Medical Centre (GB)
- Ninewells Hospital (GB)
- Manchester Academic Health Science Centre (GB)
- Western General Hospital (GB)
- John Radcliffe Hospital (GB)
- Norfolk and Norwich University Hospital (GB)
- Royal Hospital for Sick Children (GB)
- Addenbrooke's Hospital (GB)
- Guy's Hospital (GB)
- Corresponding author
- Barrett, Jeffrey C
- Anderson, Carl A
- ORCID
- Luo, Yang
- Moutsianas, Loukas
- 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
- Simmons, Alison
- 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
- Venue
- Nature Genetics
- Published
- 2017-01-09
- Volume
- 49
- Issue
- 2
- Pages
- 186-192
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5289625
- OpenAlex
- W2570471359
- Cited by
- 162
- References
- 53
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 11 · 2023: 11 · 2022: 20 · 2021: 26 · 2020: 18 · 2019: 23 · 2018: 22 · 2017: 14
- FWCI
- 13.98
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- Research Portal (King's College London) (acceptedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion)
- Funders
- Crohn's and Colitis Foundation of America
- Leona M. and Harry B. Helmsley Charitable Trust
- University of Essex
- Wellcome Trust (102974/Z/13/Z, 093885, 093885/Z/10/Z, 098051)
- Understanding Society
- National Institute for Health and Care Research (NIHR-RP-R3-12-026, CL-2014-01-005)
- King's College London
- University of Oxford
- Crohn's and Colitis UK (M10-2, M14-5, M11-1)
- Woolf Fisher Trust
- Medical Research Council (MR/J00314X/1, MR/M00533X/1, 098051, MC_UU_00008/7)
- Economic and Social Research Council (ES/H029745/1)
- NIHR Newcastle Biomedical Research Centre
- Topics
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Keywords
- inflammatory bowel disease, ulcerative colitis, Crohn's disease, genetic architecture, low-frequency variants, missense mutations, rare variants, genetic burden, heritability, genetic risk variants
- MeSH terms
- Adenylyl Cyclases, Colitis, Ulcerative, Crohn Disease, Genotype, Humans, Phenotype, Inflammatory Bowel Diseases, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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