title: Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes.
abstract: Psoriasis vulgaris (PsV) risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but its genetic architecture has yet to be fully elucidated. Here, we conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV-affected individuals and 13,589 controls of European descent by imputing class I and II human leukocyte antigen (HLA) genes from SNP genotype data. In addition, we imputed sequence variants for MICA, an MHC HLA-like gene that has been associated with PsV, to evaluate association at that locus as well. We observed that HLA-C(∗)06:02 demonstrated the lowest p value for overall PsV risk (p = 1.7 × 10(-364)). Stepwise analysis revealed multiple HLA-C(∗)06:02-independent risk variants in both class I and class II HLA genes for PsV susceptibility (HLA-C(∗)12:03, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQα1 amino acid position 53; p < 5.0 × 10(-8)), but no apparent risk conferred by MICA. We further evaluated risk of two major clinical subtypes of PsV, psoriatic arthritis (PsA; n = 3,038) and cutaneous psoriasis (PsC; n = 3,098). We found that risk heterogeneity between PsA and PsC might be driven by HLA-B amino acid position 45 (Pomnibus = 2.2 × 10(-11)), indicating that different genetic factors underlie the overall risk of PsV and the risk of specific PsV subphenotypes. Our study illustrates the value of high-resolution HLA and MICA imputation for fine mapping causal variants in the MHC.
authors.affiliation: Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-0085, Japan; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Buhm
authors.initials: B
authors.lastname: Han
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, 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.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Stuart
authors.affiliation: Institute of Clinical Molecular Biology, Kiel University, Kiel 24105, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Ellinghaus
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Trilokraj
authors.initials: T
authors.lastname: Tejasvi
authors.affiliation: Division of Rheumatology, Department of Medicine, 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: Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University of Toronto, Toronto, ON M5T 2S8, Canada.
authors.forename: Fawnda
authors.initials: F
authors.lastname: Pellett
authors.affiliation: Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University of Toronto, Toronto, ON M5T 2S8, Canada.
authors.forename: Remy
authors.initials: R
authors.lastname: Pollock
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 84112, USA.
authors.forename: Gerald G
authors.initials: GG
authors.lastname: Krueger
authors.affiliation: Department of Dermatology, Christian-Albrechts-Universität zu Kiel, Kiel 24105, 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 of Newfoundland, St. John's, NL A1C5S7, 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, Kiel University, Kiel 24105, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
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 Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.affiliation: Division of Rheumatology, Department of Medicine, 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; Toronto Western Research Institute, University of Toronto, Toronto, ON M5G 2M9, Canada.
authors.forename: Dafna D
authors.initials: DD
authors.lastname: Gladman
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: James T
authors.initials: JT
authors.lastname: Elder
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands; Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands. Electronic address: pdebakker@umcutrecht.nl.
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, Manchester M13 9PT, UK. Electronic address: soumya@broadinstitute.org.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
mesh_terms: D000595:Amino Acid Sequence; D015535:Arthritis, Psoriatic / Q000235:genetics; D001483:Base Sequence; D002874:Chromosome Mapping / Q000379:methods; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015235:HLA-B Antigens / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011565:Psoriasis / Q000145:classification / Q000235:genetics* / Q000276:immunology
chemical_list: D015235:HLA-B Antigens; D015236:HLA-C Antigens; C491620:HLA-C*06:02 antigen; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C099187:MHC class I-related chain A
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