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Nat Genet DOI:10.1038/s41588-022-01156-2

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

Publication TypeJournal Article
Year of Publication2022
AuthorsSazonovs, A, Stevens, CR, Venkataraman, GR, Yuan, K, Avila, B, Abreu, MT, Ahmad, T, Allez, M, Ananthakrishnan, AN, Atzmon, G, Baras, A, Barrett, JC, Barzilai, N, Beaugerie, L, Beecham, A, Bernstein, CN, Bitton, A, Bokemeyer, B, Chan, A, Chung, D, Cleynen, I, Cosnes, J, Cutler, DJ, Daly, A, Damas, OM, Datta, LW, Dawany, N, Devoto, M, Dodge, S, Ellinghaus, E, Fachal, L, Färkkilä, M, Faubion, W, Ferreira, M, Franchimont, D, Gabriel, SB, Ge, T, Georges, M, Gettler, K, Giri, M, Glaser, B, Goerg, S, Goyette, P, Graham, D, Hämäläinen, E, Haritunians, T, Heap, GA, Hiltunen, M, Hoeppner, M, Horowitz, JE, Irving, P, Iyer, V, Jalas, C, Kelsen, J, Khalili, H, Kirschner, BS, Kontula, K, Koskela, JT, Kugathasan, S, Kupcinskas, J, Lamb, CA, Laudes, M, Lévesque, C, Levine, AP, Lewis, JD, Liefferinckx, C, Loescher, B-S, Louis, E, Mansfield, J, May, S, McCauley, JL, Mengesha, E, Mni, M, Moayyedi, P, Moran, CJ, Newberry, RD, O'Charoen, S, Okou, DT, Oldenburg, B, Ostrer, H, Palotie, A, Paquette, J, Pekow, J, Peter, I, Pierik, MJ, Ponsioen, CY, Pontikos, N, Prescott, N, Pulver, AE, Rahmouni, S, Rice, DL, Saavalainen, P, Sands, B, R Sartor, B, Schiff, ER, Schreiber, S, L Schumm, P, Segal, AW, Seksik, P, Shawky, R, Sheikh, SZ, Silverberg, MS, Simmons, A, Skeiceviciene, J, Sokol, H, Solomonson, M, Somineni, H, Sun, D, Targan, S, Turner, D, Uhlig, HH, van der Meulen, AE, Vermeire, S, Verstockt, S, Voskuil, MD, Winter, HS, Young, J, Duerr, RH, Franke, A, Brant, SR, Cho, J, Weersma, RK, Parkes, M, Xavier, RJ, Rivas, MA, Rioux, JD, McGovern, DPB, Huang, H, Anderson, CA, Daly, MJ
Corporate AuthorsBelgium 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
JournalNat Genet
Date Published2022 Aug 29

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.


Alternate JournalNat Genet
PubMed ID36038634
Grant ListU54HG003067 / / U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) /
5UM1HG008895 / / U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) /