title: Identification of independent risk loci for Graves' disease within the MHC in the Japanese population.
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.
authors: Department of Cell Biology, Fukuoka University, Fukuoka, Japan. knakabayashi@nch.go.jp
authors: Kazuhiko
authors: K
authors: Nakabayashi
authors: Atsushi
authors: A
authors: Tajima
authors: Ken
authors: K
authors: Yamamoto
authors: Atsushi
authors: A
authors: Takahashi
authors: Kenichiro
authors: K
authors: Hata
authors: Yasuo
authors: Y
authors: Takashima
authors: Midori
authors: M
authors: Koyanagi
authors: Hirofumi
authors: H
authors: Nakaoka
authors: Takashi
authors: T
authors: Akamizu
authors: Naofumi
authors: N
authors: Ishikawa
authors: Sumihisa
authors: S
authors: Kubota
authors: Shiro
authors: S
authors: Maeda
authors: Tatsuhiko
authors: T
authors: Tsunoda
authors: Michiaki
authors: M
authors: Kubo
authors: Naoyuki
authors: N
authors: Kamatani
authors: Yusuke
authors: Y
authors: Nakamura
authors: Takehiko
authors: T
authors: Sasazuki
authors: Senji
authors: S
authors: Shirasawa
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006111:Graves Disease / Q000235:genetics*; D006801:Humans; D007564:Japan / Q000208:ethnology; D008285:Major Histocompatibility Complex / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide