Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes

Prescott, Natalie J. and Lehne, Benjamin and Stone, Kristina and Lee, James C. and Taylor, Kirstin and Knight, Jo and Papouli, Efterpi and Mirza, Muddassar M. and Simpson, Michael A. and Spain, Sarah L. and Lu, Grace and Fraternali, Franca and Bumpstead, Suzannah J. and Gray, Emma and Amar, Ariella and Bye, Hannah and Green, Peter and Chung-Faye, Guy and Hayee, Bu'Hussain and Pollok, Richard and Satsangi, Jack and Parkes, Miles and Barrett, Jeffrey C. and Mansfield, John C. and Sanderson, Jeremy and Lewis, Cathryn M. and Weale, Michael E. and Schlitt, Thomas and Mathew, Christopher G. and UK IBD Genetics Consortium (2015) Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes. PLoS Genetics, 11 (2). ISSN 1553-7390

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The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn's disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10-10, OR = 2.3[95% CI = 1.75-3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (<1%) and low frequency (1-5%) variants in 3 additional genes showed suggestive association (p<0.005) with either an increased risk (ARIH2 c.338-6C>T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis.

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Journal Article
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PLoS Genetics
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© 2015 Prescott et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
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07 Jun 2016 13:24
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18 Oct 2023 01:05