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Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility

Sazonovs, Aleksejs; Stevens, Christine R; Venkataraman, Guhan R; Yuan, Kai; Avila, Brandon; Abreu, Maria T; Ahmad, Tariq; ... Daly, Mark J; + view all (2022) Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility. Nature Genetics , 54 (9) pp. 1275-1283. 10.1038/s41588-022-01156-2. Green open access

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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.

Type: Article
Title: Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41588-022-01156-2
Publisher version: https://doi.org/10.1038/s41588-022-01156-2
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10159342
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