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

2022; Nature Portfolio; Volume: 54; Issue: 9 Linguagem: Inglês

10.1038/s41588-022-01156-2

1546-1718

Aleksejs Sazonovs, Christine Stevens, Guhan Venkataraman, Kai Yuan, Brandon E. 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 C. 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 Färkkilâ, William A. Faubion, Manuel A. R. Ferreira, Denis Franchimont, Stacey Gabriel, Tian Ge, Michel Georges, Kyle Gettler, Mamta Giri, Benjamin Gläser, Siegfried Goerg, Philippe Goyette, Daniel B. Graham, Eija Hämäläinen, Talin Haritunians, Graham Heap, Mikko Hiltunen, Marc P. Hoeppner, Julie Horowitz, Peter M. Irving, Vivek Iyer, Chaim Jalas, Judith R. Kelsen, Hamed Khalili, Barbara S. Kirschner, Kimmo Kontula, Jukka Koskela, Subra Kugathasan, Juozas Kupčinskas, Christopher A Lamb, Matthias Laudes, Chloé Lévesque, Adam P. Levine, James D. Lewis, Claire Liefferinckx, Britt-Sabina Loescher, Édouard 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 Pierik, Cyriel Y. Ponsioen, Nikolas Pontikos, Natalie J. Prescott, Ann E. Pulver, Souad Rahmouni, Daniel L Rice, Päivi Saavalainen, Bruce E. Sands, R. Balfour Sartor, Elena 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 K. Somineni, Dylan Sun, Stephan Targan, Dan Turner, Holm H. Uhlig, Andrea E. van der Meulen–de Jong, Séverine Vermeire, Sare Verstockt, Michiel Voskuil, Harland S. Winter, Justine Young, Richard H. Duerr, André Franke, Steven R. Brant, Judy H. Cho, Rinse K. Weersma, Miles Parkes, Ramnik J. Xavier, Manuel A. Rivas, John D. Rioux, Dermot McGovern, Hailiang Huang, Carl A. Anderson, Mark J. Daly,

Mycobacterium research and diagnosis

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. Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn’s disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology.