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

Belgium IBD Consortium, Cedars-Sinai IBD, International IBD Genetics Consortium, NIDDK IBD Genetics Consortium, NIHR IBD BioResource, Regeneron Genetics Center, SHARE Consortium, SPARC IBD Network, UK IBD Genetics Consortium, Aleksejs Sazonovs, Christine R. Stevens, Guhan R. Venkataraman, Kai Yuan, Brandon Avila, Maria T. Abreu, Tariq Ahmad, Matthieu Allez, Ashwin N. Ananthakrishnan, Gil Atzmon, Aris BarasJeffrey C. Barrett, Nir Barzilai, Laurent Beaugerie, Ashley Beecham, Charles N. Bernstein, Alain Bitton, Bernd Bokemeyer, Andrew Chan, Daniel Chung, Isabelle Cleynen, Jacques Cosnes, David J. Cutler, Allan Daly, Oriana M. Damas, Lisa W. Datta, Noor Dawany, Marcella Devoto, Sheila Dodge, Eva Ellinghaus, Laura Fachal, Martti Farkkila, William Faubion, Manuel Ferreira, Denis Franchimont, Stacey B. Gabriel, Tian Ge, Michel Georges, Kyle Gettler, Mamta Giri, Benjamin Glaser, Siegfried Goerg, Philippe Goyette, Daniel Graham, Eija Hämäläinen, Talin Haritunians, Graham A. Heap, Mikko Hiltunen, Michiel D. Voskuil, Rinse K. Weersma, Mark J. Daly*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)1275–1283
Number of pages22
JournalNature genetics
Volume54
DOIs
Publication statusPublished - 30-Sep-2022

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