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Pooled Sequencing of 531 Genes in Inflammatory Bowel Disease Identifies an Associated Rare Variant in BTNL2 and Implicates Other Immune Related Genes

Lookup NU author(s): Dr John Mansfield



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.

Publication metadata

Author(s): Prescott NJ, Lehne B, Stone K, Lee JC, Taylor K, Knight J, Papouli E, Mirza MM, Simpson MA, Spain SL, Lu G, Fraternali F, Bumpstead SJ, Gray E, Amar A, Bye H, Green P, Chung-Faye G, Hayee B, Pollok R, Satsangi J, Parkes M, Barrett JC, Mansfield JC, Sanderson J, Lewis CM, Weale ME, Schlitt T, Mathew CG, UK IBD Genetics Consortium

Publication type: Article

Publication status: Published

Journal: PLoS Genetics

Year: 2015

Volume: 11

Issue: 4

Online publication date: 11/02/2015

Acceptance date: 13/12/2014

Date deposited: 20/04/2016

ISSN (print): 1553-7390

ISSN (electronic): 1553-7404

Publisher: Public Library of Science


DOI: 10.1371/journal.pgen.1004955


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Funder referenceFunder name
National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London
UK National Blood Service controls by the Wellcome Trust
068545/Z/02Wellcome Trust
085475/Z/08/ZWellcome Trust Case Control Consortium
083948/Z/07/ZWellcome Trust Case Control Consortium
085475/B/08/ZWellcome Trust Case Control Consortium
094491/Z/10/ZWellcome Trust
ARC1297British Council
G0000934Medical Research Council
RG100252Royal Society