Construction of a population-specific HLA imputation reference panel and its application to Graves' disease risk in Japanese

Yukinori Okada; Yukihide Momozawa; Kyota Ashikawa; Masahiro Kanai; Koichi Matsuda; Yoichiro Kamatani; Atsushi Takahashi; Michiaki Kubo

doi:10.1038/ng.3310

Construction of a population-specific HLA imputation reference panel and its application to Graves' disease risk in Japanese

Nat Genet. 2015 Jul;47(7):798-802. doi: 10.1038/ng.3310. Epub 2015 Jun 1.

Authors

Yukinori Okada¹, Yukihide Momozawa², Kyota Ashikawa², Masahiro Kanai³, Koichi Matsuda⁴, Yoichiro Kamatani⁵, Atsushi Takahashi⁵, Michiaki Kubo²

Affiliations

¹ 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.
² Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
³ Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
⁴ Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁵ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

PMID: 26029868
DOI: 10.1038/ng.3310

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Case-Control Studies
Gene Frequency
Genetic Predisposition to Disease
Genetic Testing / standards
Genome-Wide Association Study
Graves Disease / genetics*
Histocompatibility Antigens Class I / genetics*
Histocompatibility Antigens Class II / genetics*
Humans
Japan
Linkage Disequilibrium
Mutation, Missense
Polymorphism, Single Nucleotide
Reference Standards
Risk
Sequence Analysis, DNA

Substances

Histocompatibility Antigens Class I
Histocompatibility Antigens Class II