TY - JOUR
T1 - Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility
AU - Belgium IBD Consortium
AU - Cedars-Sinai IBD
AU - International IBD Genetics Consortium
AU - NIDDK IBD Genetics Consortium
AU - NIHR IBD BioResource
AU - Regeneron Genetics Center
AU - SHARE Consortium
AU - SPARC IBD Network
AU - UK IBD Genetics Consortium
AU - Sazonovs, Aleksejs
AU - Stevens, Christine R.
AU - Venkataraman, Guhan R.
AU - Yuan, Kai
AU - Avila, Brandon
AU - Abreu, Maria T.
AU - Ahmad, Tariq
AU - Allez, Matthieu
AU - Ananthakrishnan, Ashwin N.
AU - Atzmon, Gil
AU - Baras, Aris
AU - Barrett, Jeffrey C.
AU - Barzilai, Nir
AU - Beaugerie, Laurent
AU - Beecham, Ashley
AU - Bernstein, Charles N.
AU - Bitton, Alain
AU - Bokemeyer, Bernd
AU - Chan, Andrew
AU - Chung, Daniel
AU - Cleynen, Isabelle
AU - Cosnes, Jacques
AU - Cutler, David J.
AU - Daly, Allan
AU - Damas, Oriana M.
AU - Datta, Lisa W.
AU - Dawany, Noor
AU - Devoto, Marcella
AU - Dodge, Sheila
AU - Ellinghaus, Eva
AU - Fachal, Laura
AU - Farkkila, Martti
AU - Faubion, William
AU - Ferreira, Manuel
AU - Franchimont, Denis
AU - Gabriel, Stacey B.
AU - Ge, Tian
AU - Georges, Michel
AU - Gettler, Kyle
AU - Giri, Mamta
AU - Glaser, Benjamin
AU - Goerg, Siegfried
AU - Goyette, Philippe
AU - Graham, Daniel
AU - Hämäläinen, Eija
AU - Haritunians, Talin
AU - Heap, Graham A.
AU - Hiltunen, Mikko
AU - Hoeppner, Marc
AU - Turner, Dan
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/9
Y1 - 2022/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85137084709&partnerID=8YFLogxK
U2 - 10.1038/s41588-022-01156-2
DO - 10.1038/s41588-022-01156-2
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C2 - 36038634
AN - SCOPUS:85137084709
SN - 1061-4036
VL - 54
SP - 1275
EP - 1283
JO - Nature Genetics
JF - Nature Genetics
IS - 9
ER -