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Dand, N.* ; Mucha, S.* ; Tsoi, L.C.* ; Mahil, S.K.* ; Stuart, P.E.* ; Arnold, A.* ; Baurecht, H.* ; Burden, A.D.* ; Duffin, K.C.* ; Chandran, V.* ; Curtis, C.J.* ; Das, S.* ; Ellinghaus, D.* ; Ellinghaus, E.* ; Enerbäck, C.* ; Esko, T.* ; Gladman, D.D.* ; Griffiths, C.E.M.* ; Gudjonsson, J.E.* ; Hoffman, P.* ; Homuth, G.* ; Hüffmeier, U.* ; Krueger, G.G.* ; Laudes, M.* ; Lee, S.H.* ; Lieb, W.* ; Lim, H.W.* ; Löhr, S.* ; Mrowietz, U.* ; Müller-Nurasyid, M. ; Nöthen, M.* ; Peters, A. ; Rahman, P.* ; Reis, A.* ; Reynolds, N.J.* ; Rodriguez, E.* ; Schmidt, C.O.* ; Spain, S.L.* ; Strauch, K. ; Tejasvi, T.* ; Voorhees, J.J.* ; Warren, R.B.* ; Weichenthal, M.* ; Weidinger, S.* ; Zawistowski, M.* ; Nair, R.P.* ; Capon, F.* ; Smith, C.H.* ; Trembath, R.C.* ; Abecasis, G.R.* ; Elder, J.T.* ; Franke, A.* ; Simpson, M.A.* ; Barker, J.N.*

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

Hum. Mol. Genet. 26, 4301-4313 (2017)
Verlagsversion Postprint Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Single Nucleotide Polymorphisms; Janus Kinase Inhibitor; Analysis Identifies 3; Interferon-alpha; Hla-c; Variants; Arthritis; Disease; Metaanalysis; Responses
Sprache englisch
Veröffentlichungsjahr 2017
HGF-Berichtsjahr 2017
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Zeitschrift Human Molecular Genetics
Quellenangaben Band: 26, Heft: 21, Seiten: 4301-4313 Artikelnummer: , Supplement: ,
Verlag Oxford University Press
Verlagsort Oxford
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Genetic Epidemiology (IGE)
Institute of Epidemiology (EPI)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30202 - Environmental Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-504100-001
G-504000-010
G-504000-001
DOI 10.1093/hmg/ddx328
WOS ID WOS:000413453900018
Scopus ID 85034220948
PubMed ID 28973304
Erfassungsdatum 2017-10-10
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