Journal article
Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility
- Abstract:
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
-
-
(Preview, Accepted manuscript, pdf, 2.8MB, Terms of use)
-
- Publisher copy:
- 10.1038/s41588-022-01156-2
Authors
+ NIDDK NIH HHS
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- Funder identifier:
- https://ror.org/00adh9b73
- Grant:
- K01 DK114379
+ NIHR Academy
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- Funder identifier:
- https://ror.org/02nv4he32
- Grant:
- NIHR-RP-R3-12-026
+ Wellcome Trust
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- Funder identifier:
- https://ror.org/029chgv08
- Grant:
- 102974/Z/13/Z
- 219523/Z/19/Z
+ Medical Research Council
More from this funder
- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- MC_PC_MR/S025952/1
- MR/M00533X/1
+ UK Research and Innovation
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- Funder identifier:
- https://ror.org/001aqnf71
- Grant:
- MR/S036377/1
- Publisher:
- Springer Nature
- Journal:
- Nature Genetics More from this journal
- Volume:
- 54
- Issue:
- 9
- Pages:
- 1275-1283
- Place of publication:
- United States
- Publication date:
- 2022-08-29
- Acceptance date:
- 2022-07-12
- DOI:
- EISSN:
-
1546-1718
- ISSN:
-
1061-4036
- Pmid:
-
36038634
- Language:
-
English
- Pubs id:
-
1277499
- Local pid:
-
pubs:1277499
- Deposit date:
-
2024-09-13
Terms of use
- Copyright holder:
- Sazonovs et al.
- Copyright date:
- 2022
- Rights statement:
- © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
- Notes:
- This is the accepted manuscript version of the article. The final version is available online from Springer Nature at https://dx.doi.org/10.1038/s41588-022-01156-2
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