Association mapping of inflammatory bowel disease loci to single variant resolution

Hailiang Huang; Ming Fang; Luke Jostins; Masa U Mirkov; Gabrielle Boucher; Carl A Anderson; Vibeke Andersen; Isabelle Cleynen; Adrian Cortes; Francois Crins; Mauro D'Amato; Valerie Deffontaine; Julia Dimitrieva; Elisa Docampo; Mahmoud Elansary; Kyle Kai-How Farh; Andre Franke; Ann-Stephan Gori; Philippe Goyette; Jonas Halfvarson; Talin Haritunians; Jo Knight; Ian C Lawrance; Charlie W Lees; Edouard Louis; Rob Mariman; Theo Meuwissen; Myriam Mni; Yukihide Momozawa; Miles Parkes; Sarah L Spain; Emilie Theatre; Gosia Trynka; Jack Satsangi; Suzanne van Sommeren; Severine Vermeire; Ramnik J Xavier; International IBD Genetics Consortiu

doi:10.1101/028688

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bioRxiv · 10.1101/028688

Association mapping of inflammatory bowel disease loci to single variant resolution

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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.

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Hailiang Huang, Ming Fang, Luke Jostins, Masa U Mirkov, Gabrielle Boucher, Carl A Anderson, Vibeke Andersen, Isabelle Cleynen, Adrian Cortes, Francois Crins, Mauro D'Amato, Valerie Deffontaine, Julia Dimitrieva, Elisa Docampo, Mahmoud Elansary, Kyle Kai-How Farh, Andre Franke, Ann-Stephan Gori, Philippe Goyette, Jonas Halfvarson, Talin Haritunians, Jo Knight, Ian C Lawrance, Charlie W Lees, Edouard Louis, Rob Mariman, Theo Meuwissen, Myriam Mni, Yukihide Momozawa, Miles Parkes, Sarah L Spain, Emilie Theatre, Gosia Trynka, Jack Satsangi, Suzanne van Sommeren, Severine Vermeire, Ramnik J Xavier, International IBD Genetics Consortiu. 2015-10-08. Association mapping of inflammatory bowel disease loci to single variant resolution. https://doi.org/10.1101/028688

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