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

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68 Citations (Scopus)

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, I, 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.

Original languageEnglish
Pages (from-to)798-802
Number of pages5
JournalNature Genetics
Volume47
Issue number7
DOIs
Publication statusPublished - 26-06-2015

All Science Journal Classification (ASJC) codes

  • Genetics

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    Okada, Y., Momozawa, Y., Ashikawa, K., Kanai, M., Matsuda, K., Kamatani, Y., Takahashi, A., & Kubo, M. (2015). Construction of a population-specific HLA imputation reference panel and its application to Graves' disease risk in Japanese. Nature Genetics, 47(7), 798-802. https://doi.org/10.1038/ng.3310