Association mapping of inflammatory bowel disease loci to single variant resolution

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.

Genetics: Clues in the code

“…The International Inflammatory Bowel Disease Genetics Consortium has recently completed a three-year 'fine-mapping' effort that has pinpointed 45 specific genetic variants that contribute to the disease. The data suggest that some of these variants lie outside the coding and regulatory regions of genes -in parts of the genome that have no known function 5 .…”

Autoimmune diseases — connecting risk alleles with molecular traits of the immune system

“…For example, for the IL2RA gene, which encodes a subunit of the IL-2 cytokine receptor, researchers found a new variant that is partially linked to previously reported variants, as well as two additional independently associated variants 41 . More recently, researchers fine-mapped 18 IBD risk loci, including previously reported coding variants as well as additional protein-coding, intronic and intergenic variants, to a single likely causal variant 69 . Specifically, the SNP rs6062496, in the intron of the TNFRSF6B gene, overlaps an open chromatin region and is predicted to alter a transcription factor binding site for early B-cell factor 1 (EBF1), which is implicated in B cell identity 69 .…”

“…More recently, researchers fine-mapped 18 IBD risk loci, including previously reported coding variants as well as additional protein-coding, intronic and intergenic variants, to a single likely causal variant 69 . Specifically, the SNP rs6062496, in the intron of the TNFRSF6B gene, overlaps an open chromatin region and is predicted to alter a transcription factor binding site for early B-cell factor 1 (EBF1), which is implicated in B cell identity 69 . The ImmunoChip has also been useful in the discovery of novel associations and fine-mapping in other auto immune diseases, including psoriasis, juvenile idiopathic arthritis, RA, ankylosing spondylitis and autoimmune thyroid disease 41,70–74 .…”

TMEM258 Is a Component of the Oligosaccharyltransferase Complex Controlling ER Stress and Intestinal Inflammation

“…To date, GWASs have implicated more than 200 loci in IBD (Jostins et al, 2012; Liu et al, 2015), yet many of these loci contain multiple genes that are in linkage disequilibrium (LD), and conclusive identification of the IBD risk gene in most loci has been challenging. In a few notable examples, causal variants associated with IBD risk have been identified by GWAS (e.g., NOD2 and ATG16L1 ) (Huang, 2015). In the vast majority of IBD loci, more targeted approaches are necessary to establish causality.…”