Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease
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Abstract
Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.
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PLCG2 GOF polymorphisms have been recently associated with other disorders, such as inflammatory bowel disease and resistance of chronic lymphocytic leukaemia cells to the BTK inhibitor ibrutinib.
“PLCG2 GOF polymorphisms have also been recently associated with other disorders, such as inflammatory bowel disease [114] and resistance of chronic lymphocytic leukaemia cells to the BTK inhibitor ibrutinib [99, 115]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [114]
The paper reports two likely functional PLCG2 missense variants associated with inflammatory bowel disease (section labelled Abstract; page unavailable). It does not establish that those IBD-associated variants are gain-of-function. The ibrutinib-resistance clause has separate citations and is not attributed to this paper. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThis convergence and enrichment provides reassurance that genetic associations will coalesce around molecular and cellular processes with a core role in pathogenesis.
“This provides reassurance that, even as the number of association signals for a given disease proliferates, the genetic associations uncovered will coalesce around molecular and cellular processes with a core role in pathogenesis62,63.”
From A brief history of human disease genetics (2020) · cites this paper as [63]
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Self-citation
- Authors
- de Lange, K. M., Moutsianas, L., Lee, J. C., Lamb, C. A., Luo, Y., Kennedy, N. A., Jostins, L., Rice, D. L., Gutierrez-Achury, J., Ji, S.-G., Heap, G., Nimmo, E. R., Edwards, C., Henderson, P., Mowat, C., Sanderson, J., Satsangi, J., Simmons, A., Wilson, D. C., Tremelling, M., Hart, A., Mathew, C. G., Newman, W. G., Parkes, M., Lees, C. W., Uhlig, H., Hawkey, C., Prescott, N. J., Ahmad, T., Mansfield, J. C., Anderson, C. A., & Barrett, J. C.
- Affiliations
- Wellcome Sanger Institute (GB)
- Addenbrooke's Hospital (GB)
- Newcastle University (GB)
- Broad Institute (US)
- University of Exeter (GB)
- Centre for Human Genetics (GB)
- Western General Hospital (GB)
- Torbay Hospital (GB)
- Royal Hospital for Sick Children (GB)
- Ninewells Hospital (GB)
- St Thomas' Hospital (GB)
- John Radcliffe Hospital (GB)
- Norfolk and Norwich University Hospital (GB)
- St Mark's Hospital (GB)
- Guy's Hospital (GB)
- Manchester Academic Health Science Centre (GB)
- Queen's Medical Centre (GB)
- Corresponding author
- Anderson, Carl A
- Barrett, Jeffrey C
- ORCID
- Moutsianas, Loukas
- Lee, James C
- Lamb, Christopher A
- Luo, Yang
- Kennedy, Nicholas A
- Rice, Daniel L
- Ji, Sun-Gou
- Heap, Graham
- Edwards, Cathryn
- Henderson, Paul
- Mowat, Craig
- Sanderson, Jeremy
- Simmons, Alison
- Wilson, David C
- Hart, Ailsa
- Mathew, Christopher G
- Newman, William G
- Parkes, Miles
- Lees, Charlie W
- Uhlig, Holm
- Hawkey, Chris
- Prescott, Natalie J
- Ahmad, Tariq
- Mansfield, John C
- Anderson, Carl A
- Barrett, Jeffrey C
- Venue
- Nature Genetics
- Published
- 2017-01-09
- Volume
- 49
- Issue
- 2
- Pages
- 256-261
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5289481
- OpenAlex
- W2571503386
- Cited by
- 1,445
- References
- 58
- Citations by year
- 2026: 118 · 2025: 163 · 2024: 257 · 2023: 215 · 2022: 161 · 2021: 172 · 2020: 132 · 2019: 111 · 2018: 81 · 2017: 31 · 2016: 2 · 2015: 1
- FWCI
- 12.80
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Research Explorer (The University of Manchester) (submittedVersion, other-oa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- University of Essex
- Wellcome Trust (102974/Z/13/Z, 094491/Z/10/Z, 093885, 093885/Z/10/Z, 098051)
- Understanding Society
- National Institute for Health and Care Research (NIHR-RP-R3-12-026, ACF-2014-23-002, CL-2014-01-005)
- King's College London
- Crohn's and Colitis UK (M11-2, M10-2, M14-5, M11-1)
- Woolf Fisher Trust
- Medical Research Council (MR/J00314X/1, MR/M00533X/1, MR/N01104X/1, 098051, MR/N01104X/2, MC_UU_00008/7)
- Economic and Social Research Council (ES/H029745/1)
- NIHR Newcastle Biomedical Research Centre
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › 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, immune activation, genetic susceptibility loci, CD49d, ITGB8, CD11a, ICAM-1, PLCγ2, SLAMF8, missense mutations, therapeutic target
- MeSH terms
- Alleles, Humans, Inflammation, Inflammatory Bowel Diseases, Integrins, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study
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