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

Journal article


Publication Details

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, Hueffmeier U, Krueger GG, Laudes M, Lee SH, Lieb W, Lim HW, Loehr S, Mrowietz U, Mueller-Nurayid M, Noethen 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
Journal: Human Molecular Genetics
Publication year: 2017
Volume: 26
Journal issue: 21
Pages range: 4301-4313
ISSN: 0964-6906


Abstract


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.



External institutions with authors

Christian-Albrechts-Universität zu Kiel
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU)
Henry Ford Health System (HFHS)
King’s College London
Linköping University
Memorial University of Newfoundland (MUN)
National Institute for Health Research
Newcastle University
Rheinische Friedrich-Wilhelms-Universität Bonn
Universität Basel
Universitätsklinikum Göttingen
Universitätsklinikum Schleswig-Holstein (UKSH)
Universitätsmedizin Greifswald / Universitätsklinikum Greifswald
University of Glasgow
University of Manchester
University of Michigan
University of Tartu
University of Toronto
University of Utah


How to cite

APA:
Dand, N., Mucha, S., Tsoi, L.C., Mahil, S.K., Stuart, P.E., Arnold, A.,... Barker, J.N. (2017). Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling. Human Molecular Genetics, 26(21), 4301-4313. https://dx.doi.org/10.1093/hmg/ddx328

MLA:
Dand, Nick, et al. "Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling." Human Molecular Genetics 26.21 (2017): 4301-4313.

BibTeX: 

Last updated on 2018-08-10 at 08:29