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Nat Genet. 2017 Feb;49(2):186-192. doi: 10.1038/ng.3761. Epub 2017 Jan 9.

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

Author information

1
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
2
Division of Genetics and Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
3
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
4
Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK.
5
Christ Church, University of Oxford, St Aldates, UK.
6
Precision Medicine Exeter, University of Exeter, Exeter, UK.
7
IBD Pharmacogenetics, Royal Devon and Exeter Foundation Trust, Exeter, UK.
8
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne.
9
Department of Gastroenterology, Torbay Hospital, Torbay, Devon, UK.
10
Department of Medicine, St Mark's Hospital, Harrow, Middlesex, UK.
11
Nottingham Digestive Diseases Centre, Queens Medical Centre, Nottingham, UK.
12
Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK.
13
Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK.
14
Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK.
15
The Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.
16
Gastrointestinal Unit, Wester General Hospital University of Edinburgh, Edinburgh, UK.
17
Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
18
Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
19
Gastroenterology & General Medicine, Norfolk and Norwich University Hospital, Norwich, UK.
20
Translational Gastroenterology Unit and the Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
21
Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK.
22
Child Life and Health, University of Edinburgh, Edinburgh, Scotland, UK.
23
Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge, UK.
24
Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King's College London, Guy's Hospital, London, UK.
25
Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of Witwatersrand, South Africa.
#
Contributed equally

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.

PMID:
28067910
PMCID:
PMC5289625
DOI:
10.1038/ng.3761
[Indexed for MEDLINE]
Free PMC Article

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