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

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 (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Book Volume: 26

Pages Range: 4301-4313

Journal Issue: 21

DOI: 10.1093/hmg/ddx328

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.

Authors with CRIS profile

Involved external institutions

King’s College London United Kingdom (GB) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Christian-Albrechts-Universität zu Kiel Germany (DE) University of Michigan United States (USA) (US) National Institute for Health Research United Kingdom (GB) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) University of Manchester United Kingdom (GB) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich Germany (DE) Universitätsmedizin Greifswald / Universitätsklinikum Greifswald Germany (DE) Newcastle University United Kingdom (GB) Memorial University of Newfoundland (MUN) Canada (CA) Henry Ford Health System (HFHS) United States (USA) (US) University of Utah United States (USA) (US) Universitätsklinikum Göttingen Germany (DE) Universität Basel Switzerland (CH) University of Toronto Canada (CA) University of Tartu Estonia (EE) Linköping University Sweden (SE) University of Glasgow United Kingdom (GB)

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.

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