Journal Article

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

Goerg, Siegfried, Moran, Christopher J., Ferreira, Manuel, Rice, Daniel L., May, Sandra, Mengesha, Emebet, Iyer, Vivek, Sazonovs, Aleksejs, Turner, Dan, McGovern, Dermot P. B., Kelsen, Judith, Irving, Peter, Franke, Andre, Glaser, Benjamin, Pierik, Marieke J., Somineni, Hari, Okou, David T., Cosnes, Jacques, Sartor, R. Balfour, Chan, Andrew, Levine, Adam P., McCauley, Jacob L., Liefferinckx, Claire, Ge, Tian, Parkes, Miles, Lévesque, Chloé, Heap, Graham A., Mansfield, John, Graham, Daniel, Weersma, Rinse K., Fachal, Laura, Lamb, Christopher A., Solomonson, Matthew, Faubion, William, Devoto, Marcella, Anderson, Carl A., Chung, Daniel, Giri, Mamta, Simmons, Alison, Schiff, Elena R., Cutler, David J., Lewis, James D., Atzmon, Gil, Palotie, Aarno, Damas, Oriana M., Haritunians, Talin, Louis, Edouard, Beecham, Ashley, Hiltunen, Mikko, Uhlig, Holm H., Kontula, Kimmo, Beaugerie, Laurent, Koskela, Jukka T., Silverberg, Mark S., Kupcinskas, Juozas, Mni, Myriam, O’Charoen, Sirimon, Daly, Allan, Dodge, Sheila, Franchimont, Denis, Georges, Michel, Shawky, Rasha, Khalili, Hamed, Verstockt, Sare, Rahmouni, Souad, Cho, Judy, Olde

2022

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group,Springer Science and Business Media LLC
• Subject: 631/208 / 692/699 / Agriculture / Animal Genetics and Genomics / Autophagy / Biobanks / Biomedical and Life Sciences / Biomedicine / Cancer Research / Consortia / Crohn Disease - genetics / Crohn's disease / Datasets / Gene Function / Gene sequencing / Genes / Genetic Predisposition to Disease / Genetics / Genetics & genetic processes / Genome-wide association studies / Genome-Wide Association Study / Genomes / Génétique & processus génétiques / Human Genetics / Humans / Immune system / Inflammatory bowel disease / Life sciences / Mesenchyme / Meta-analysis / Pathogenesis / Polymorphism, Single Nucleotide - genetics / Population control / Sciences du vivant