Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes

Yukinori Okada; Buhm Han; Lam C Tsoi; Philip E Stuart; Eva Ellinghaus; Trilokraj Tejasvi; Vinod Chandran; Fawnda Pellett; Remy Pollock; Anne M Bowcock; Gerald G Krueger; Michael Weichenthal; John J Voorhees; Proton Rahman; Peter K Gregersen; Andre Franke; Rajan P Nair; Gonçalo R Abecasis; Dafna D Gladman; James T Elder; Paul I W de Bakker; Soumya Raychaudhuri

doi:10.1016/j.ajhg.2014.07.002

Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes

Am J Hum Genet. 2014 Aug 7;95(2):162-72. doi: 10.1016/j.ajhg.2014.07.002. Epub 2014 Jul 31.

Authors

Yukinori Okada¹, Buhm Han², Lam C Tsoi³, Philip E Stuart⁴, Eva Ellinghaus⁵, Trilokraj Tejasvi⁴, Vinod Chandran⁶, Fawnda Pellett⁷, Remy Pollock⁷, Anne M Bowcock⁸, Gerald G Krueger⁹, Michael Weichenthal¹⁰, John J Voorhees⁴, Proton Rahman¹¹, Peter K Gregersen¹², Andre Franke⁵, Rajan P Nair⁴, Gonçalo R Abecasis³, Dafna D Gladman¹³, James T Elder¹⁴, Paul I W de Bakker¹⁵, Soumya Raychaudhuri¹⁶

Affiliations

¹ 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.
² 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.
³ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
⁴ Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁵ Institute of Clinical Molecular Biology, Kiel University, Kiel 24105, Germany.
⁶ 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.
⁷ Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University of Toronto, Toronto, ON M5T 2S8, Canada.
⁸ National Heart and Lung Institute, Imperial College, London SW7 2AZ, UK.
⁹ Department of Dermatology, University of Utah, Salt Lake City, UT 84112, USA.
¹⁰ Department of Dermatology, Christian-Albrechts-Universität zu Kiel, Kiel 24105, Germany.
¹¹ Memorial University of Newfoundland, St. John's, NL A1C5S7, Canada.
¹² The Feinstein Institute for Medical Research, North Shore - Long Island Jewish Health System, Manhasset, NY 11030, USA.
¹³ 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.
¹⁴ Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI 48105, USA.
¹⁵ 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: [email protected].
¹⁶ 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: [email protected].

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.

Publication types

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

MeSH terms

Amino Acid Sequence
Arthritis, Psoriatic / genetics
Base Sequence
Chromosome Mapping / methods
Genetic Association Studies
Genetic Predisposition to Disease
Genotype
HLA-B Antigens / genetics
HLA-C Antigens / genetics
Histocompatibility Antigens Class I / genetics*
Histocompatibility Antigens Class II / genetics*
Humans
Major Histocompatibility Complex / genetics*
Polymorphism, Single Nucleotide
Psoriasis / classification
Psoriasis / genetics*
Psoriasis / immunology

Substances

HLA-B Antigens
HLA-C Antigens
HLA-C*06:02 antigen
Histocompatibility Antigens Class I
Histocompatibility Antigens Class II
MHC class I-related chain A

Abstract

Publication types

MeSH terms

Substances

Grants and funding