Fine-mapping inflammatory bowel disease loci to single-variant resolution

Abstract

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. Results of fine-mapping 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals and several new fine-mapping methods. Genome-wide association studies for inflammatory bowel disease (IBD) have identified over 200 associated loci but the causal variants at only several of these individual loci have been resolved. Here, Hailiang Hang and colleagues report fine-mapping of 94 of these IBD susceptibility loci using high-density genotyping in 67,852 individuals. They apply several new fine-mapping methods and identify 139 independent associations, 18 of which are resolved to a single causal variant with >95% certainty. This provides an example of how fine-mapping with high-density genotyping in large sample sizes is able to resolve causal variants at GWAS loci, an approach that may be used for other complex traits. To review the detailed fine-mapping results and annotations, a customizable browser is available at http://finemapping.broadinstitute.org .

Cite this article

Huang, H., Fang, M., Jostins, L. et al. Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature 547, 173–178 (2017). https://doi.org/10.1038/nature22969

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