title: Identification of BACH2 as a susceptibility gene for Graves' disease in the Chinese Han population based on a three-stage genome-wide association study.
abstract: The BACH2 gene regulates B cell differentiation and function and has been reported to be a shared susceptibility gene for several autoimmune diseases. Our previous genome-wide association study (GWAS) indicated that several single nucleotide polymorphisms (SNPs) in the BACH2 gene are associated with Graves' disease (GD) in the Chinese Han population; however, the association did not achieve genome-wide significance levels. Recently, this association of BACH2 with GD was confirmed in Caucasians in the UK population, but fine mapping in this region has not yet been reported. Here, we provide a refined analysis of a 331-kb region in the BACH2 gene, which harbors 359 SNPs, using GWAS data from 1,442 GD patients and 1,468 controls. The SNPs rs2474619 and rs9344996 were implied as the independent variants associated with GD by forward and two-locus logistic regression analysis. We genotyped eight out of 10 tagSNPs with P < 1 × 10(-3) in 3,508 GD patients and 3,209 controls, the results also showed that rs2474619 was independently associated with GD in the combined population from GWAS and the second stage (P = 1.81 × 10(-5)). The rs2474619 and rs9344996 were further genotyped in the third stage cohorts, and rs2474619 showed evidence of association with GD at genome-wide significance levels in the combined population (P = 3.28 × 10(-8), odds ratio = 1.13). The association of rs9344996 with GD can be explained by its linkage to rs2474619 in the combined population. Our study clearly demonstrated that BACH2 is a susceptibility gene for GD in the Chinese Han population and further supported rs2474619, in intron 2 of BACH2, is the best association signal with GD. However, the mechanism by which BACH2 confers increased risk of GD requires further study.
authors.affiliation: State Key Laboratory of Medical Genomics, Molecular Medicine Center, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Hai-Ning
authors.initials: HN
authors.lastname: Wang
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Gu
authors.forename: Shao-Ying
authors.initials: SY
authors.lastname: Yang
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Ye
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Pan
authors.forename: Shuang-Xia
authors.initials: SX
authors.lastname: Zhao
authors.forename: Li-Qiong
authors.initials: LQ
authors.lastname: Xue
authors.forename: Hui-Jun
authors.initials: HJ
authors.lastname: Xie
authors.forename: Sha-Sha
authors.initials: SS
authors.lastname: Yu
authors.forename: Cui-Cui
authors.initials: CC
authors.lastname: Guo
authors.forename: Wen-Hua
authors.initials: WH
authors.lastname: Du
authors.forename: Jun
authors.initials: J
authors.lastname: Liang
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Zhang
authors.forename: Guo-Yue
authors.initials: GY
authors.lastname: Yuan
authors.forename: Chang-Gui
authors.initials: CG
authors.lastname: Li
authors.forename: Qing
authors.initials: Q
authors.lastname: Su
authors.forename: Guan-Qi
authors.initials: GQ
authors.lastname: Gao
authors.forename: Huai-Dong
authors.initials: HD
authors.lastname: Song
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics*; D002681:China; D017931:DNA Primers; D005006:Ethnicity / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006111:Graves Disease / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C491123:BACH2 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D017931:DNA Primers