title: An X chromosome-wide association analysis identifies variants in GPR174 as a risk factor for Graves' disease.
abstract: BACKGROUND
  Graves' disease is a female preponderant autoimmune illness and the contribution of the X chromosome to its risk has long been appreciated. However, no X-linked susceptibility loci have been indentified from recent genome-wide association studies (GWAS).
  
  
  METHODS
  We re-examined the X chromosome data from our recent GWAS for Graves' disease by including males that were previously excluded from the X chromosome analyses. The data were analysed using logistic regression analysis including sex as a covariate, and an additive method assuming X chromosome inactivation, implemented in snpMatrix.
  
  
  RESULTS
  A cluster of single nucleotide polymorphism (SNPs) at Xq21.1 was found showing association with genome-wide significance, among which rs3827440 was a non-synonymous SNP of GPR174 (P(logistic regression)= 9.52×10(-8); P(snpMatrix)=4.60×10(-9); OR=1.76, 95% CI 1.45 to 2.13). The association was reproduced in an independent sample collection set including 4564 Graves' disease cases and 3968 sex matched controls (combined P(logistic regression)=5.53×10(-21); combined P(snpMatrix)=4.26×10(-22); OR=1.69, 95% CI 1.53 to 1.86). Notably, GPR174 was widely expressed in immune related tissues and rs3827440 genotypes were associated with distinct mRNA levels (p=0.002). GPR174 did not show sex biased gene expression in our expression analysis. Resequencing study suggested the contribution of some rare variants in the GPR174 gene region to disease risk with a collapsing p value of 1.16×10(-3).
  
  
  CONCLUSIONS
  The finding of an X-linked risk locus for Graves' disease expands our understanding of the role of the X chromosome in disease susceptibility.
authors.affiliation: Department of Genetics, Chinese National Human Genome Center, Bldg. 1, 250 BiBo Road, Shanghai 201203, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Chu
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Miao
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Shou
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.forename: Peng-Peng
authors.initials: PP
authors.lastname: Yang
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Bai
authors.forename: Kai-Yue
authors.initials: KY
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.forename: Qi
authors.initials: Q
authors.lastname: Hua
authors.forename: Wen-Dong
authors.initials: WD
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Wang
authors.forename: Jin-Xiu
authors.initials: JX
authors.lastname: Shi
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Huai-Dong
authors.initials: HD
authors.lastname: Song
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
mesh_terms: D000483:Alleles; D041321:Chromosomes, Human, X / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006111:Graves Disease / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D008297:Male; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D012307:Risk Factors
chemical_list: C581018:GPR174 protein, human; D043562:Receptors, G-Protein-Coupled
keywords: Complex traits; Endocrinology; Genetics; Genome-wide; Thyroid disease