title: Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis.
abstract: Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging. Here, we conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA) in a Japanese population (6,244 RA cases and 23,731 controls) population by using HLA imputation, followed by a multi-ethnic validation study including east Asian and European populations (n = 7,097 and 23,149, respectively). Our study identified an independent risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk (p = 1.4 × 10(-9)), which demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression. Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns in HLA-DOA and HLA-DRB1, explaining the observed HLA-DOA variant risk heterogeneity among ethnicities, which was most evident in the Japanese population. Although previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility to disease, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to the understanding of HLA immunology in human diseases and suggests the value of incorporating additional ancestry in MHC fine-mapping.
authors.affiliation: Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 113-0034 Tokyo, Japan; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Department of Statistical Genetics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan. Electronic address: yokada@sg.med.osaka-u.ac.jp.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Akari
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-0054, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo 162-0054, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ikari
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Terao
authors.affiliation: Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo 162-0054, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kochi
authors.affiliation: Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ohmura
authors.affiliation: Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Higasa
authors.affiliation: Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Akiyama
authors.affiliation: Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Kyota
authors.initials: K
authors.lastname: Ashikawa
authors.affiliation: Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 113-0034 Tokyo, Japan; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kanai
authors.affiliation: Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 113-0034 Tokyo, Japan; Pharmaceutical Discovery Research Laboratories, Teijin Pharma, Hino 191-8512, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Hirata
authors.affiliation: Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 113-0034 Tokyo, Japan; Advanced Medicinal Research Laboratories, Tsukuba Research Institute, Ono Pharmaceutical, Tsukuba 300-4247, Japan.
authors.forename: Naomasa
authors.initials: N
authors.lastname: Suita
authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117549.
authors.forename: Yik-Ying
authors.initials: YY
authors.lastname: Teo
authors.affiliation: Department of Rheumatology and Immunology, Shanghai Changzheng Hospital and The Second Military Medical University, Shanghai 200433, China.
authors.forename: Huji
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 04763, South Korea.
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Bae
authors.affiliation: Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Momozawa
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 108-8639 Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuda
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-0054, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Momohara
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-0054, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Taniguchi
authors.affiliation: Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.affiliation: Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Tsuneyo
authors.initials: T
authors.lastname: Mimori
authors.affiliation: Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland 4072, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Partners Center for Personalized Genetic Medicine, Boston, MA 02115, USA; Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PL, UK.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.affiliation: Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-0054, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yamanaka
authors.affiliation: Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kamatani
authors.affiliation: Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics*; D044466:Asian People / Q000235:genetics*; D001323:Autoantibodies; D002956:Citrulline; D005006:Ethnicity / Q000235:genetics; D005060:Europe / Q000208:ethnology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006681:HLA-D Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D007564:Japan / Q000208:ethnology; D015810:Linkage Disequilibrium / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D001323:Autoantibodies; D006681:HLA-D Antigens; D059811:HLA-DRB1 Chains; D002956:Citrulline