Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci.
Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genome-wide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genome-wide significance (P<5 × 10(-8)). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3) and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2-dependent target of IL-17 signalling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies.
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Lam C
LC
Tsoi
Division of Genetics and Molecular Medicine, King's College London, London WC2R 2LS, UK.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
Sarah L
SL
Spain
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
Eva
http://orcid.org/0000-0003-2914-3382
E
Ellinghaus
Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Philip E
PE
Stuart
Division of Genetics and Molecular Medicine, King's College London, London WC2R 2LS, UK.
Francesca
F
Capon
Neuroscience Research, Centre for Addiction and Mental Health, Toronto, Ontario, Canada M5T 1R8.|National Institute for Health Research (NIHR), Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust, London SE1 9RT, UK.
Jo
J
Knight
Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Trilokraj
T
Tejasvi
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Hyun M
HM
Kang
Division of Genetics and Molecular Medicine, King's College London, London WC2R 2LS, UK.
Michael H
MH
Allen
Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Sylviane
S
Lambert
Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Stefan W
SW
Stoll
Department of Dermatology, University Hospital, Schleswig-Holstein, Christian-Albrechts-University, 24105 Kiel, Germany.
Stephan
S
Weidinger
Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Johann E
JE
Gudjonsson
Department of Pathophysiology, Centre of Translational Medicine and Centre for Translational Genomics, University of Tartu, 50409 Tartu, Estonia.
Sulev
http://orcid.org/0000-0001-6087-6643
S
Koks
Department of Dermatology and Venereology, University of Tartu, 50409 Tartu, Estonia.
Külli
K
Kingo
Estonian Genome Center, University of Tartu, 51010 Tartu, Estonia.
Tonu
T
Esko
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Sayantan
S
Das
Estonian Genome Center, University of Tartu, 51010 Tartu, Estonia.
Andres
A
Metspalu
Department of Dermatology, University Hospital, Schleswig-Holstein, Christian-Albrechts-University, 24105 Kiel, Germany.
Michael
M
Weichenthal
Department of Dermatology, Linköping University, SE-581 83 Linköping, Sweden.
Charlotta
C
Enerback
Department of Dermatology, University of Utah, Salt Lake City, Utah 84132, USA.
Gerald G
GG
Krueger
Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109, USA.
John J
JJ
Voorhees
Department of Medicine, Division of Rheumatology, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada M5T 2S8.
Vinod
V
Chandran
Department of Medicine, Division of Dermatology, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada M5T 2S8.
Cheryl F
CF
Rosen
Department of Medicine, Memorial University, St John's, Newfoundland, Canada A1C 5B8.
Proton
P
Rahman
Department of Medicine, Division of Rheumatology, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada M5T 2S8.
Dafna D
DD
Gladman
Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
Andre
http://orcid.org/0000-0002-6301-6363
A
Reis
Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Rajan P
RP
Nair
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
Andre
A
Franke
Division of Genetics and Molecular Medicine, King's College London, London WC2R 2LS, UK.
Jonathan N W N
JNWN
Barker
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Goncalo R
GR
Abecasis
Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AD, UK.
Richard C
RC
Trembath
Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109, USA.|Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan 48105, USA.
James T
JT
Elder
D048868:Adaptor Proteins, Signal Transducing; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics; D020381:Interleukin-17 / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D011565:Psoriasis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D020672:I-kappa B Proteins; D020381:Interleukin-17; C417234:NFKBIZ protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; C414202:TRAF3IP2 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins