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Hum Mol Genet. 2017 Nov 1;26(21):4301-4313. doi: 10.1093/hmg/ddx328.

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

Author information

1
Division of Genetics and Molecular Medicine, Faculty of Life Sciences & Medicine, King's College London, London, UK.
2
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
3
Department of Dermatology.
4
Department of Computational Medicine & Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
5
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
6
St John's Institute of Dermatology, Faculty of Life Sciences & Medicine, King's College London, London, UK.
7
Clinic and Polyclinic of Dermatology, University Medicine Greifswald, Greifswald, Germany.
8
Department of Dermatology, Venereology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
9
Institute of Infection, Inflammation and Immunity, University of Glasgow, Glasgow, UK.
10
Department of Dermatology, University of Utah, Salt Lake City, UT, USA.
11
Department of Medicine.
12
Department of Laboratory Medicine and Pathobiology.
13
Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
14
Krembil Research Institute, University Health Network, Toronto, ON, Canada.
15
NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK.
16
Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
17
Division of Cell Biology and Dermatology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
18
Estonian Biobank, Estonian Genome Center, University of Tartu, Tartu, Estonia.
19
Dermatology Centre, Salford Royal Hospital, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
20
Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
21
Institute of Human Genetics, University of Bonn, Bonn, Germany.
22
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
23
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
24
I. Department of Medicine.
25
Institute of Epidemiology and Biobank PopGen, Christian-Albrechts-University of Kiel, Kiel, Germany.
26
Department of Dermatology, Henry Ford Hospital, Detroit, MI, USA.
27
Institute of Genetic Epidemiology, Helmholtz Zentrum Munich, Neuherberg, Germany.
28
Memorial University of Newfoundland, St. John's, NL, Canada.
29
Dermatological Sciences, Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, UK.
30
Department of Dermatology, Royal Victoria Infirmary, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
31
Institute for Community Medicine, Study of Health in Pomerania/KEF, University Medicine Greifswald, Greifswald, Germany.
32
Dermatology Centre, Salford Road NHS Foundation Trust, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
33
Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
34
Ann Arbor Veterans Hospital, Ann Arbor, MI, USA.

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.

PMID:
28973304
PMCID:
PMC5886170
DOI:
10.1093/hmg/ddx328
[Indexed for MEDLINE]
Free PMC Article

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