Identification of independent risk loci for Graves' disease within the MHC in the Japanese population

J Hum Genet. 2011 Nov;56(11):772-8. doi: 10.1038/jhg.2011.99. Epub 2011 Sep 8.

Abstract

To identify genetic variants that confer the risk of Graves' disease (GD) in the Japanese population, we conducted a two-stage genome-wide association study (GWAS) using 1119 Japanese individuals with GD and 2718 unrelated controls, and a subsequent replication study using independent 432 GD cases and 1157 controls. We identified 34 single nucleotide polymorphisms (SNPs) to be significantly associated with GD in the GWAS phase. Twenty-two out of 34 SNPs remained positive in the replication study. All 22 SNPs were located within the major histocompatibility complex (MHC) locus on chromosome 6p21. No strong long-range linkage disequilibrium (LD) was observed among the 22 SNPs, indicating independent involvement of multiple loci within the MHC with the risk of GD. Multivariate stepwise logistic regression analysis selected rs3893464, rs4313034, rs3132613, rs4248154, rs2273017, rs9394159 and rs4713693, as markers for independent risk loci for GD. The analysis of LD between these seven SNPs and tagging SNPs for GD-associated human leukocyte antigen (HLA) alleles in the Japanese population (HLA-DPB1(*)0501 and HLA-A(*)0206) demonstrated that all of and five of seven SNPs were not in strong LD with HLA-DPB1(*)0501 and HLA-A(*)0206, respectively. Although causal variants remain to be identified, our results demonstrate the existence of multiple GD susceptibility loci within the MHC region.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Asian Continental Ancestry Group / genetics
  • Case-Control Studies
  • Gene Frequency
  • Genetic Loci*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Graves Disease / genetics*
  • Humans
  • Japan / ethnology
  • Major Histocompatibility Complex / genetics*
  • Polymorphism, Single Nucleotide