Fine-mapping inflammatory bowel disease loci to single variant resolution

By Hailiang Huang, M. Fang, L. Jostins, Masa Umicevic Mirkov, G. Boucher, C. Anderson, V. Andersen, I. Cleynen, A. Cortes, François Crins and 36 more. 2017

540 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Genetics, Surgery

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Epidemiology

In Genetics

Citations in the corpus

Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease. (2019, methodology): “candidate cytokine gene(s) per unique locus (de Lange et al., 2017; Huang et al., 2017; Jostins et al., 2012) MD-IBD spontaneous colitis in mouse targeting in pre-clinical models used in clinics or tested in clinical trials”
Cellular and inter-cellular rewiring of the human colon during ulcerative colitis (2019, background): “Defining IBD associations and candidate risk genes—We compiled a list of IBD, UC, and CD associations from recent large-scale IBD genome-wide association and finemapping studies (de Lange et al., 2017; Huang et al., 2017; Jostins et al., 2012; Liu et al., 2015).”
Comparative genetic architectures of schizophrenia in East Asian and European populations (2018, unknown): “Bayesian fine-mapping approaches 2,43,86,87 have been widely used for studies of a single ancestry.”
Functionally-informed fine-mapping and polygenic localization of complex trait heritability (2019, result): “We validated the motivation for performing functionally informed fine-mapping by verifying that fine-mapped SNPs are enriched for functional annotations, as previously shown for auto-immune diseases 7,8,10 and blood traits 12 (using nonfunctionally informed SuSiE to avoid biasing the results).”
Integrative omics for health and disease (2018, background): “…genetic variation data, a challenge exists in mapping SNPs to the affected gene: in some cases, the effect of the variant is clear — such as a frameshift variant in an immune-response-related gene, NOD2 , in Crohn’s disease 27 — but more often, the affected gene for a variant may be ambiguous 28 .”
The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019 (2018, background): “The Catalog’s data have many applications, for example, to identify causal variants (17), understand disease mechanisms, analyse expression quantitative trait loci (eQTL) (18,19) and establish targets for novel therapies (8,20).”