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.


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


  • Histocompatibility Antigens Class I
  • Histocompatibility Antigens Class II