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

TitelExome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.
MedientypJournal Article
Jahr der Veröffentlichung2017
AutorenDand N, Mucha S, Tsoi LC, Mahil SK, Stuart PE, Arnold A, Baurecht H, A Burden D, Duffin KCallis, Chandran V, Curtis CJ, Das S, Ellinghaus D, Ellinghaus E, Enerback C, Esko T, Gladman DD, Griffiths CEM, Gudjonsson JE, Hoffman P, Homuth G, Hüffmeier U, Krueger GG, Laudes M, Lee SHyuck, Lieb W, Lim HW, Löhr S, Mrowietz U, Müller-Nurayid M, Nöthen 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
JournalHum Mol Genet
Volume26
Ausgabe21
Pagination4301-4313
Datum der Veröffentlichung2017 Nov 01
ISSN1460-2083
SchlüsselwörterAlleles, Case-Control Studies, Cohort Studies, Exome, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Interferon-Induced Helicase, IFIH1, Male, Polymorphism, Single Nucleotide, Psoriasis, Risk Factors, Tumor Necrosis Factor Ligand Superfamily Member 15, TYK2 Kinase, Whole Exome Sequencing
Zusammenfassung

<p>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.</p>

DOI10.1093/hmg/ddx328
Alternate JournalHum. Mol. Genet.
PubMed ID28973304
Grant ListR01 AR042742 / AR / NIAMS NIH HHS / United States
R01 AR050511 / AR / NIAMS NIH HHS / United States
R01 AR063611 / AR / NIAMS NIH HHS / United States
R01 AR065183 / AR / NIAMS NIH HHS / United States