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.

Original publication

DOI

10.1038/nature22969

Type

Journal article

Journal

Nature

Volume

547

Pages

173 - 178

Keywords

Adolescent, Adult, Aged, Aged, 80 and over, Binding Sites, Chromatin, Colitis, Ulcerative, Crohn Disease, Epigenesis, Genetic, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Inflammatory Bowel Diseases, Linkage Disequilibrium, Male, Middle Aged, Quantitative Trait Loci, Smad3 Protein, Transcription Factors, Young Adult