Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants

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Abstract

Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size >39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFκB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8 ⁺ T-cells and CD4 ⁺ T-cells including T _H0, T _H1 and T _H17). The identified loci explain ∼28% of the genetic heritability and generate a discriminatory genetic risk score (AUC=0.76 in our sample) that is significantly correlated with age at onset ( p=2 × 10 ⁻⁸⁹). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis.

Abstract

Psoriasis is an immune-mediated skin disease with a complex genetic architecture. Here, Elder and colleagues identify 16 novel psoriasis susceptibility loci using GWAS meta-analysis with a combined effective sample size of over 39,000 individuals.

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Most cited references 31

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Psoriatic arthritis: epidemiology, clinical features, course, and outcome.

D D Gladman, C Antoni, P. Mease … (2005)

Psoriatic arthritis (PsA) has been defined as a unique inflammatory arthritis associated with psoriasis. Its exact prevalence is unknown, but estimates vary from 0.3% to 1% of the population. The clinical features described initially are recognised by most experienced clinicians, although they are most distinct in early disease. Initially, PsA typically presents as an oligoarticular and mild disease. However, with time PsA becomes polyarticular, and it is a severe disease in at least 20% of patients. Patients with PsA who present with polyarticular disease are at risk for disease progression. In addition to progression of clinical and radiological damage, health related quality of life is reduced among patients with PsA. It important to note that patients included in recent drug trials resemble patients followed prospectively in a clinic.

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The immunogenetics of Psoriasis: A comprehensive review.

Jamie L. Harden, James G. Krueger, Anne Bowcock (2015)

Psoriasis vulgaris is a common, chronic inflammatory skin disease with a complex etiology involving genetic risk factors and environmental triggers. Here we describe the many known genetic predispositions of psoriasis with respect to immune genes and their encoded pathways in psoriasis susceptibility. These genes span an array of functions that involve antigen presentation (HLA-Cw6, ERAP1, ERAP2, MICA), the IL-23 axis (IL12Bp40, IL23Ap19, IL23R, JAK2, TYK2), T-cell development and T-cells polarization (RUNX1, RUNX3, STAT3, TAGAP, IL4, IL13), innate immunity (CARD14, c-REL, TRAF3IP2, DDX58, IFIH1), and negative regulators of immune responses (TNIP1, TNFAIP3, NFKBIA, ZC3H12C, IL36RN, SOCS1). The contribution of some of these gene products to psoriatic disease has also been revealed in recent years through targeting of key immune components, such as the Th17/IL-23 axis which has been highly successful in disease treatment. However, many of the genetic findings involve immune genes with less clear roles in psoriasis pathogenesis. This is particularly the case for those genes involved in innate immunity and negative regulation of immune specific pathways. It is possible that risk alleles of these genes decrease the threshold for the initial activation of the innate immune response. This could then lead to the onslaught of the pathogenic adaptive immune response known to be active in psoriatic skin. However, precisely how these various genes affect immunobiology need to be determined and some are speculated upon in this review. These novel genetic findings also open opportunities to explore novel therapeutic targets and potentially the development of personalized medicine, as well as discover new biology of human skin disease.

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Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris.

Tilo Henseler, Enno Christophers (1985)

In 2,147 patients suffering from psoriasis, evaluation of the age of onset revealed two peaks, one occurring at the age of 16 years (female) or 22 years (males) and a second peak at the age of 60 years (female) or 57 years (males). Human lymphocyte antigen (HLA) tissue typing in 112 randomly assigned patients showed that HLA-Cw6, known to be at disequilibrium in psoriasis, is present in 85.3% of patients with early onset. In contrast, 14.7% patients with late onset showed this marker. Parents (father or mother) were affected in approximately half of the patients with early onset and in none belonging to the group with late onset. Furthermore, psoriasis in patients with early onset follows an irregular course and shows a strong tendency to become generalized. On the basis of clearly defined criteria (e.g., age of onset, heritability, and clinical course of disease), nonpustular psoriasis shows two distinct forms, one of which is hereditary, with early onset, and the other is sporadic and occurs in older age.

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Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group

ISSN (Electronic): 2041-1723

Publication date (Electronic): 24 May 2017

Publication date Collection: 2017

Volume: 8

Electronic Location Identifier: 15382

Affiliations

[1 ]Department of Dermatology, University of Michigan Medical School , Ann Arbor, Michigan 48109, USA

[2 ]Department of Biostatistics, Center for Statistical Genetics, University of Michigan , Ann Arbor, Michigan 48109, USA

[3 ]Department of Computational Medicine & Bioinformatics, University of Michigan Medical School , Ann Arbor, Michigan 48109, USA

[4 ]23andMe, Inc., Mountain View , California 94041, USA

[5 ]Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel , Kiel 24105, Germany

[6 ]St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London , London SE1 9RT, UK

[7 ]Department of Medicine, Division of Rheumatology, University of Toronto , Toronto, Ontario, Canada M5S 1A8

[8 ]Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University of Toronto , Toronto, Ontario, Canada M5T 2S8

[9 ]Department of Dermatology, University of Utah , Salt Lake City, Utah 84132, USA

[10 ]Department of Dermatology, Linköping University , Linköping SE-581 83, Sweden

[11 ]Estonian Genome Center, University of Tartu , Tartu 51010, Estonia

[12 ]Broad Institute of MIT and Harvard , Cambridge, Massachusetts 02142, USA

[13 ]Institute of Human Genetics, University of Bonn , Bonn 53127, Germany

[14 ]Division of Medical Genetics, Department of Biomedicine, University of Basel , Basel 4031, Switzerland

[15 ]Dermatology Clinic, Tartu University Hospital, Department of Dermatology and Venereology, University of Tartu , Tartu 50417, Estonia

[16 ]Department of Pathophysiology, Centre of Translational Medicine and Centre for Translational Genomics, University of Tartu , Tartu 50411, Estonia

[17 ]Department of Reproductive Biology, Estonian University of Life Sciences , Tartu 51006, Estonia

[18 ]Department of Dermatology, Henry Ford Hospital , Detroit, Michigan 48202, USA

[19 ]Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel , Kiel 24105, Germany

[20 ]Memorial University, St. John's , Newfoundland, Newfoundland and Labrador, Canada A1B 3X9

[21 ]Institute of Human Genetics, FAU Erlangen-Nürnberg , Erlangen 91054, Germany

[22 ]Ann Arbor Veterans Affairs Hospital , Ann Arbor, Michigan 48105, USA

[23 ]Department of Medical and Molecular Genetics, King's College London , London WC2R 2LS, UK

Author notes

[a ] jelder@ 123456umich.edu

[*]

These authors contributed equally to this work.

Author information

Sayantan Das http://orcid.org/0000-0001-6346-1590

Matthew Zawistowski http://orcid.org/0000-0002-3005-083X

Eva Ellinghaus http://orcid.org/0000-0003-2914-3382

Nick Dand http://orcid.org/0000-0002-1805-6278

Andre Franke http://orcid.org/0000-0003-1530-5811

Andre Reis http://orcid.org/0000-0002-6301-6363

Michael Weichenthal http://orcid.org/0000-0002-9060-4961

Article

Publisher Item ID: ncomms15382

DOI: 10.1038/ncomms15382

PMC ID: 5458077

PubMed ID: 28537254

SO-VID: 1ff07afe-f0b4-4026-8aff-f9e38ddaaad8

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History

Date received : 07 July 2016

Date accepted : 27 March 2017

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Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants

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Most cited references 31

Psoriatic arthritis: epidemiology, clinical features, course, and outcome.

The immunogenetics of Psoriasis: A comprehensive review.

Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris.

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