Journal
NATURE GENETICS
Volume 54, Issue 9, Pages 1275-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41588-022-01156-2
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Funding
- US National Institutes of Health [U54HG003067, 5UM1HG008895]
- Wellcome Trust [206194, 108413/A/15/D]
- Leona M. & Harry B. Helmsley Charitable Trust [2015PG-IBD001]
- NHGRI of the NIH [R01HG010140]
- NIH Center for Multi-and Trans-ethnic Mapping of Mendelian and Complex Diseases [5U01HG009080]
- NIDDK [K01DK114379, P30DK043351, P01DK046763, U01DK062413, R01DK104844]
- Stanley Center for Psychiatric Research
- Martin Schlaff, James Brooks
- B. Hasso Family Foundation
- NIHR Oxford Biomedical Research Centre
- Leona M. and Harry B. Helmsley Charitable Trust
- Academy of Finland Centre of Excellence in Complex Disease Genetics [312074, 336824]
- NIH [R01HG010140, 5U01HG009080, DK062431, DK062432, DK087694, K23DK117054, R01DK111843, P01DK094779, DK062420]
- Academy of Finland (AKA) [336824] Funding Source: Academy of Finland (AKA)
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Genome-wide association studies have identified new risk variants and susceptibility genes for Crohn's disease. These studies highlight the crucial role of immune cells and autophagy in the development of Crohn's disease, and also emphasize the importance of mesenchymal cells in intestinal inflammation.
Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation. Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn's disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology.
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