Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility.
Sazonovs 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., Farkkila 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., Sartor RB., Schiff ER., Schreiber S., Schumm LP., 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., Belgium IBD Consortium None., Cedars-Sinai IBD None., International IBD Genetics Consortium None., NIDDK IBD Genetics Consortium None., NIHR IBD BioResource None., Regeneron Genetics Center None., SHARE Consortium None., SPARC IBD Network None., UK IBD Genetics Consortium None., 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.
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.