title: Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture.
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.
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Stuart
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Rajan P
authors.initials: RP
authors.lastname: Nair
authors.affiliation: 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.
authors.forename: Lam C
authors.initials: LC
authors.lastname: Tsoi
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI 48105, USA.
authors.forename: Trilokraj
authors.initials: T
authors.lastname: Tejasvi
authors.affiliation: Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Sayantan
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Hyun Min
authors.initials: HM
authors.lastname: Kang
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Ellinghaus
authors.affiliation: 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.
authors.forename: Vinod
authors.initials: V
authors.lastname: Chandran
authors.affiliation: Department of Dermatology, University of Utah, Salt Lake City, UT 84132, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Callis-Duffin
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Ike
authors.affiliation: Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Wen
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Cell Biology and Dermatology, Linköping University, 581 83 Linköping, Sweden.
authors.forename: Charlotta
authors.initials: C
authors.lastname: Enerbäck
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Johann E
authors.initials: JE
authors.lastname: Gudjonsson
authors.affiliation: 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.
authors.forename: Sulev
authors.initials: S
authors.lastname: Kõks
authors.affiliation: Dermatology Clinic, Tartu University Hospital, Department of Dermatology and Venereology, University of Tartu, 50417 Tartu, Estonia.
authors.forename: Külli
authors.initials: K
authors.lastname: Kingo
authors.affiliation: Estonian Genome Center, University of Tartu, 51010 Tartu, Estonia.
authors.forename: Tõnu
authors.initials: T
authors.lastname: Esko
authors.affiliation: Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mrowietz
authors.affiliation: Institute of Human Genetics, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Reis
authors.affiliation: 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.
authors.forename: H Erich
authors.initials: HE
authors.lastname: Wichmann
authors.affiliation: 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.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany.
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: 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.
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
authors.affiliation: Department of Dermatology, Venereology and Allergology, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kunz
authors.affiliation: Saint Paul Rheumatology, Eagan, MN 55121, USA.
authors.forename: Elvia G
authors.initials: EG
authors.lastname: Moreta
authors.affiliation: Seattle Rheumatology Associates, 601 Broadway, Suite 600, Seattle, WA 98122, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Mease
authors.affiliation: Allergy, Immunology, and Rheumatology Division, University of Rochester Medical Center, Rochester, NY 14623, USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Ritchlin
authors.affiliation: National Heart and Lung Institute, Imperial College, London SW7 2AZ, UK.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Bowcock
authors.affiliation: Department of Dermatology, University of Utah, Salt Lake City, UT 84132, USA.
authors.forename: Gerald G
authors.initials: GG
authors.lastname: Krueger
authors.affiliation: Department of Dermatology, Henry Ford Hospital, Detroit, MI 48202, USA.
authors.forename: Henry W
authors.initials: HW
authors.lastname: Lim
authors.affiliation: Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Weidinger
authors.affiliation: Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Weichenthal
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Voorhees
authors.affiliation: Memorial University, St. John's, NL A1C 5B8, Canada.
authors.forename: Proton
authors.initials: P
authors.lastname: Rahman
authors.affiliation: The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030, USA.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: 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.
authors.forename: Dafna D
authors.initials: DD
authors.lastname: Gladman
authors.affiliation: Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.affiliation: 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.
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
mesh_terms: D000293:Adolescent; D000328:Adult; D015535:Arthritis, Psoriatic / Q000235:genetics* / Q000473:pathology; D001499:Bayes Theorem; D016022:Case-Control Studies; D055233:Cornified Envelope Proline-Rich Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015236:HLA-C Antigens / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011565:Psoriasis / Q000235:genetics* / Q000473:pathology; D018123:Receptors, Interleukin / Q000235:genetics; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D055233:Cornified Envelope Proline-Rich Proteins; D004268:DNA-Binding Proteins; D015236:HLA-C Antigens; C515500:IL23R protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D018123:Receptors, Interleukin; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
keywords: genome-wide association study; joint diseases; psoriasis; psoriatic arthritis; skin diseases