Fine-mapping inflammatory bowel disease loci to single-variant resolution.
Huang H., Fang M., Jostins L., Umićević Mirkov M., Boucher G., Anderson CA., Andersen V., Cleynen I., Cortes A., Crins F., D'Amato M., Deffontaine V., Dmitrieva J., Docampo E., Elansary M., Farh KK-H., Franke A., Gori A-S., Goyette P., Halfvarson J., Haritunians T., Knight J., Lawrance IC., Lees CW., Louis E., Mariman R., Meuwissen T., Mni M., Momozawa Y., Parkes M., Spain SL., Théâtre E., Trynka G., Satsangi J., van Sommeren S., Vermeire S., Xavier RJ., International Inflammatory Bowel Disease Genetics Consortium None., Weersma RK., Duerr RH., Mathew CG., Rioux JD., McGovern DPB., Cho JH., Georges M., Daly MJ., Barrett JC.
Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 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 last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.