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

Authors

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 Baras, Jeffrey 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, Marc Hoeppner, Julie E Horowitz, Peter Irving, Vivek Iyer, Chaim Jalas, Judith Kelsen, Hamed Khalili, Barbara S Kirschner, Kimmo Kontula, Jukka T Koskela, Subra Kugathasan, Juozas Kupcinskas, Christopher A Lamb, Matthias Laudes, Chloé Lévesque, Adam P Levine, James D Lewis, Claire Liefferinckx, Britt-Sabina Loescher, Edouard Louis, John Mansfield, Sandra May, Jacob L McCauley, Emebet Mengesha, Myriam Mni, Paul Moayyedi, Christopher J Moran, Rodney D Newberry, Sirimon O’Charoen, David T Okou, Bas Oldenburg, Harry Ostrer, Aarno Palotie, Jean Paquette, Joel Pekow, Inga Peter, Marieke J Pierik, Cyriel Y Ponsioen, Nikolas Pontikos, Natalie Prescott, Ann E Pulver, Souad Rahmouni, Daniel L Rice, Päivi Saavalainen, Bruce Sands, R Balfour Sartor, Elena R Schiff, Stefan Schreiber, L Philip Schumm, Anthony W Segal, Philippe Seksik, Rasha Shawky, Shehzad Z Sheikh, Mark S Silverberg, Alison Simmons, Jurgita Skeiceviciene, Harry Sokol, Matthew Solomonson, Hari Somineni, Dylan Sun, Stephan Targan, Dan Turner, Holm H Uhlig, Andrea E van der Meulen, Séverine Vermeire, Sare Verstockt, Michiel D Voskuil, Harland S Winter, Justine Young, Richard H Duerr, Andre Franke, Steven R Brant, Judy Cho, Rinse K Weersma, Miles Parkes, Ramnik J Xavier, Manuel A Rivas, John D Rioux, Dermot P B McGovern, Hailiang Huang, Carl A Anderson, Mark J Daly

Year of publication

2022

Journal

NAT GENET

Volume

-

Issue

-

ISSN

1061-4036

Impact factor

30.8

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.