title: Construction of a population-specific HLA imputation reference panel and its application to Graves' disease risk in Japanese.
abstract: To fine map association signals of human leukocyte antigen (HLA) variants in the major histocompatibility complex (MHC) region, we constructed a Japanese population-specific reference panel (n = 908). We conducted trans-ancestry comparisons of linkage disequilibrium (LD) and haplotype structure for HLA variants using an entropy-based LD measurement, ɛ, and a visualization tool to capture high-dimensional variables. Our Japanese reference panel exhibited stronger LD between HLA genes than European or other East Asian populations, characterized by one population-specific common long-range HLA haplotype. We applied HLA imputation to genome-wide association study (GWAS) data for Graves' disease in Japanese (n = 9,003) and found that amino acid polymorphisms of multiple class I and class II HLA genes independently contribute to disease risk (HLA-DPB1, HLA-A, HLA-B and HLA-DRB1; P < 2.3 × 10(-6)), with the strongest impact at HLA-DPB1 (P = 1.6 × 10(-42)). Our study illustrates the value of population-specific HLA reference panels.
authors.affiliation: 1] Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. [2] Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Momozawa
authors.affiliation: Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, 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, Tokyo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kanai
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Koichi
authors.identifier: 0000000172922686
authors.initials: K
authors.lastname: Matsuda
authors.affiliation: Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kamatani
authors.affiliation: Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
mesh_terms: D016022:Case-Control Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000592:standards; D055106:Genome-Wide Association Study; D006111:Graves Disease / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D012015:Reference Standards; D012306:Risk; D017422:Sequence Analysis, DNA
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II