Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture

Philip E Stuart; Rajan P Nair; Lam C Tsoi; Trilokraj Tejasvi; Sayantan Das; Hyun Min Kang; Eva Ellinghaus; Vinod Chandran; Kristina Callis-Duffin; Robert Ike; Yanming Li; Xiaoquan Wen; Charlotta Enerbäck; Johann E Gudjonsson; Sulev Kõks; Külli Kingo; Tõnu Esko; Ulrich Mrowietz; Andre Reis; H Erich Wichmann; Christian Gieger; Per Hoffmann; Markus M Nöthen; Juliane Winkelmann; Manfred Kunz; Elvia G Moreta; Philip J Mease; Christopher T Ritchlin; Anne M Bowcock; Gerald G Krueger; Henry W Lim; Stephan Weidinger; Michael Weichenthal; John J Voorhees; Proton Rahman; Peter K Gregersen; Andre Franke; Dafna D Gladman; Gonçalo R Abecasis; James T Elder

doi:10.1016/j.ajhg.2015.10.019

Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture

Am J Hum Genet. 2015 Dec 3;97(6):816-36. doi: 10.1016/j.ajhg.2015.10.019. Epub 2015 Nov 28.

Authors

Philip E Stuart¹, Rajan P Nair¹, Lam C Tsoi², Trilokraj Tejasvi³, Sayantan Das⁴, Hyun Min Kang⁴, Eva Ellinghaus⁵, Vinod Chandran⁶, Kristina Callis-Duffin⁷, Robert Ike⁸, Yanming Li⁴, Xiaoquan Wen⁴, Charlotta Enerbäck⁹, Johann E Gudjonsson¹, Sulev Kõks¹⁰, Külli Kingo¹¹, Tõnu Esko¹², Ulrich Mrowietz¹³, Andre Reis¹⁴, H Erich Wichmann¹⁵, Christian Gieger¹⁶, Per Hoffmann¹⁷, Markus M Nöthen¹⁷, Juliane Winkelmann¹⁸, Manfred Kunz¹⁹, Elvia G Moreta²⁰, Philip J Mease²¹, Christopher T Ritchlin²², Anne M Bowcock²³, Gerald G Krueger⁷, Henry W Lim²⁴, Stephan Weidinger¹³, Michael Weichenthal¹³, John J Voorhees¹, Proton Rahman²⁵, Peter K Gregersen²⁶, Andre Franke⁵, Dafna D Gladman⁶, Gonçalo R Abecasis⁴, James T Elder²⁷

Affiliations

¹ Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
² Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
³ Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI 48105, USA.
⁴ Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
⁶ Department of Medicine, Division of Rheumatology, University of Toronto, Toronto, ON M5T 2S8, Canada; Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University of Toronto, Toronto, ON M5T 2S8, Canada.
⁷ Department of Dermatology, University of Utah, Salt Lake City, UT 84132, USA.
⁸ Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁹ Department of Clinical and Experimental Medicine, Division of Cell Biology and Dermatology, Linköping University, 581 83 Linköping, Sweden.
¹⁰ Department of Pathophysiology, Centre of Translational Medicine and Centre for Translational Genomics, University of Tartu, 50411 Tartu, Estonia; Department of Reproductive Biology, Estonian University of Life Sciences, 51014 Tartu, Estonia.
¹¹ Dermatology Clinic, Tartu University Hospital, Department of Dermatology and Venereology, University of Tartu, 50417 Tartu, Estonia.
¹² Estonian Genome Center, University of Tartu, 51010 Tartu, Estonia.
¹³ Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
¹⁴ Institute of Human Genetics, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
¹⁵ Institute of Epidemiology I, Helmholtz Zentrum Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University, 81377 Munich, Germany; Institute of Medical Statistics and Epidemiology, Technical University Munich, 80333 Munich, Germany.
¹⁶ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
¹⁷ Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany.
¹⁸ Neurologische Klinik and Poliklinik, Klinikum rechts der Isar, Technische Universität München, 80333 Munich, Germany; Institute of Neurogenomics, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
¹⁹ Department of Dermatology, Venereology and Allergology, University of Leipzig, 04103 Leipzig, Germany.
²⁰ Saint Paul Rheumatology, Eagan, MN 55121, USA.
²¹ Seattle Rheumatology Associates, 601 Broadway, Suite 600, Seattle, WA 98122, USA.
²² Allergy, Immunology, and Rheumatology Division, University of Rochester Medical Center, Rochester, NY 14623, USA.
²³ National Heart and Lung Institute, Imperial College, London SW7 2AZ, UK.
²⁴ Department of Dermatology, Henry Ford Hospital, Detroit, MI 48202, USA.
²⁵ Memorial University, St. John's, NL A1C 5B8, Canada.
²⁶ The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030, USA.
²⁷ Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI 48105, USA. Electronic address: jelder@umich.edu.

Abstract

Psoriasis vulgaris (PsV) is a common inflammatory and hyperproliferative skin disease. Up to 30% of people with PsV eventually develop psoriatic arthritis (PsA), an inflammatory musculoskeletal condition. To discern differences in genetic risk factors for PsA and cutaneous-only psoriasis (PsC), we carried out a genome-wide association study (GWAS) of 1,430 PsA case subjects and 1,417 unaffected control subjects. Meta-analysis of this study with three other GWASs and two targeted genotyping studies, encompassing a total of 9,293 PsV case subjects, 3,061 PsA case subjects, 3,110 PsC case subjects, and 13,670 unaffected control subjects of European descent, detected 10 regions associated with PsA and 11 with PsC at genome-wide (GW) significance. Several of these association signals (IFNLR1, IFIH1, NFKBIA for PsA; TNFRSF9, LCE3C/B, TRAF3IP2, IL23A, NFKBIA for PsC) have not previously achieved GW significance. After replication, we also identified a PsV-associated SNP near CDKAL1 (rs4712528, odds ratio [OR] = 1.16, p = 8.4 × 10(-11)). Among identified psoriasis risk variants, three were more strongly associated with PsC than PsA (rs12189871 near HLA-C, p = 5.0 × 10(-19); rs4908742 near TNFRSF9, p = 0.00020; rs10888503 near LCE3A, p = 0.0014), and two were more strongly associated with PsA than PsC (rs12044149 near IL23R, p = 0.00018; rs9321623 near TNFAIP3, p = 0.00022). The PsA-specific variants were independent of previously identified psoriasis variants near IL23R and TNFAIP3. We also found multiple independent susceptibility variants in the IL12B, NOS2, and IFIH1 regions. These results provide insights into the pathogenetic similarities and differences between PsC and PsA.

Keywords: genome-wide association study; joint diseases; psoriasis; psoriatic arthritis; skin diseases.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adolescent
Adult
Arthritis, Psoriatic / genetics*
Arthritis, Psoriatic / pathology
Bayes Theorem
Case-Control Studies
Cornified Envelope Proline-Rich Proteins / genetics
DNA-Binding Proteins / genetics
Female
Genetic Loci*
Genetic Predisposition to Disease*
Genome-Wide Association Study
HLA-C Antigens / genetics
Humans
Intracellular Signaling Peptides and Proteins / genetics
Linkage Disequilibrium
Male
Nuclear Proteins / genetics
Polymorphism, Single Nucleotide*
Psoriasis / genetics*
Psoriasis / pathology
Receptors, Interleukin / genetics
Tumor Necrosis Factor Receptor Superfamily, Member 9 / genetics
Tumor Necrosis Factor alpha-Induced Protein 3

Substances

Cornified Envelope Proline-Rich Proteins
DNA-Binding Proteins
HLA-C Antigens
IL23R protein, human
Intracellular Signaling Peptides and Proteins
Nuclear Proteins
Receptors, Interleukin
TNFRSF9 protein, human
Tumor Necrosis Factor Receptor Superfamily, Member 9
TNFAIP3 protein, human
Tumor Necrosis Factor alpha-Induced Protein 3

Associated data

dbGaP/PHS000982.V1.P1

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding