Author:
Huang Hailiang,Fang Ming,Jostins Luke,Mirkov Masa U,Boucher Gabrielle,Anderson Carl A,Andersen Vibeke,Cleynen Isabelle,Cortes Adrian,Crins Francois,D'Amato Mauro,Deffontaine Valerie,Dimitrieva Julia,Docampo Elisa,Elansary Mahmoud,Farh Kyle Kai-How,Franke Andre,Gori Ann-Stephan,Goyette Philippe,Halfvarson Jonas,Haritunians Talin,Knight Jo,Lawrance Ian C,Lees Charlie W,Louis Edouard,Mariman Rob,Meuwissen Theo,Mni Myriam,Momozawa Yukihide,Parkes Miles,Spain Sarah L,Theatre Emilie,Trynka Gosia,Satsangi Jack,van Sommeren Suzanne,Vermeire Severine,Xavier Ramnik J,Weersma Rinse K,Duerr Richard H,Mathew Christopher G,Rioux John D,McGovern Dermot PB,Cho Judy H,Georges Michel,Daly Mark J,Barrett Jeffrey C,
Abstract
Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammatory disorder that affects millions worldwide. Genome-wide association studies (GWAS) have identified 200 IBD-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 IBD loci using high-density genotyping in 67,852 individuals. Of the 139 independent associations identified in these regions, 18 were pinpointed to a single causal variant with >95% certainty, and an additional 27 associations to a single variant with >50% certainty. These 45 variants are significantly enriched for protein-coding changes (n=13), direct disruption of transcription factor binding sites (n=3) and tissue specific epigenetic marks (n=10), with the latter category showing enrichment in specific immune cells among associations stronger in CD and gut mucosa among associations stronger in UC. The results of this study suggest that high-resolution, fine-mapping in large samples can convert many GWAS discoveries into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.
Publisher
Cold Spring Harbor Laboratory