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Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling

Lookup NU author(s): Professor Nick Reynolds

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


Abstract

© 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.


Publication metadata

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

Year: 2017

Volume: 26

Issue: 21

Pages: 4301-4313

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

URL: https://doi.org/10.1093/hmg/ddx328

DOI: 10.1093/hmg/ddx328


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