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Lookup NU author(s): Professor Nick Reynolds
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author 2017. Published by Oxford University Press. All rights reserved. Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P=1.50×10-8, OR=1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency < 0.01) via gene-wide aggregation testing (IFIH1: pburden=2.53×10-7, OR=0.707; TYK2: pburden=6.17×10-4, OR=0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.
Author(s): Dand N, Mucha S, Tsoi LC, Mahil SK, Stuart PE, Arnold A, Baurecht H, Burden AD, Duffin KC, Chandran V, Curtis CJ, Das S, Ellinghaus D, Ellinghaus E, Enerback C, Esko T, Gladman DD, Griffiths CEM, Gudjonsson JE, Hoffman P, Homuth G, Huffmeier U, Krueger GG, Laudes M, Lee SH, Lieb W, Lim HW, Lohr S, Mrowietz U, Muller-Nurayid M, Nothen M, Peters A, Rahman P, Reis A, Reynolds NJ, Rodriguez E, Schmidt CO, Spain SL, Strauch K, Tejasvi T, Voorhees JJ, Warren RB, Weichenthal M, Weidinger S, Zawistowski M, Nair RP, Capon F, Smith CH, Trembath RC, Abecasis GR, Elder JT, Franke A, Simpson MA, Barker JN
Publication type: Article
Publication status: Published
Journal: Human Molecular Genetics
Print publication date: 01/11/2017
Online publication date: 24/08/2017
Acceptance date: 18/08/2017
Date deposited: 18/12/2017
ISSN (print): 0964-6906
ISSN (electronic): 1460-2083
Publisher: Oxford University Press
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