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

Huang, Hailiang and Fang, Ming and Jostins, Luke and Umićević Mirkov, Maša and Boucher, Gabrielle and Anderson, Carl A and Andersen, Vibeke and Cleynen, Isabelle and Cortes, Adrian and Crins, François and D'Amato, Mauro and Deffontaine, Valérie and Dmitrieva, Julia and Docampo, Elisa and Elansary, Mahmoud and Farh, Kyle Kai-How and Franke, Andre and Gori, Ann-Stephan and Goyette, Philippe and Halfvarson, Jonas and Haritunians, Talin and Knight, Jo and Lawrance, Ian C and Lees, Charlie W and Louis, Edouard and Mariman, Rob and Meuwissen, Theo and Mni, Myriam and Momozawa, Yukihide and Parkes, Miles and Spain, Sarah L and Théâtre, Emilie and Trynka, Gosia and Satsangi, Jack and van Sommeren, Suzanne and Vermeire, Severine and Xavier, Ramnik J and Weersma, Rinse K and Duerr, Richard H and Mathew, Christopher G and Rioux, John D and McGovern, Dermot P B and Cho, Judy H and Georges, Michel and Daly, Mark J and Barrett, Jeffrey C and , International Inflammatory Bowel Disease Genetics Consortium (2017) Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature, 547 (7662). pp. 173-178. ISSN 0028-0836

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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.

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06 Jul 2017 14:32
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15 Sep 2023 00:35