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An X chromosome-wide association analysis identifies variants in GPR174 as a risk factor for Graves’ disease
  1. Xun Chu1,2,
  2. Min Shen2,
  3. Fang Xie2,
  4. Xiao-Jing Miao2,
  5. Wei-Hua Shou2,
  6. Lin Liu3,
  7. Peng-Peng Yang2,
  8. Ya-Nan Bai2,
  9. Kai-Yue Zhang2,
  10. Lin Yang2,
  11. Qi Hua2,
  12. Wen-Dong Liu4,
  13. Yan Dong5,
  14. Hai-Feng Wang2,
  15. Jin-Xiu Shi2,
  16. Yi Wang2,
  17. Huai-Dong Song1,
  18. Sai-Juan Chen1,6,
  19. Zhu Chen1,6,
  20. Wei Huang1,2
  1. 1State Key Laboratory of Medical Genomics, Ruijin Hospital Affiliated to Shanghai Jiaotong University (SJTU) School of Medicine, Shanghai, China
  2. 2Department of Genetics, Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center and Shanghai Academy of Science & Technology, Shanghai, China
  3. 3Department of Endocrinology, Weifang People's Hospital, Shandong Province, China
  4. 4Department of Blood Transfusion, The Affiliated Hospital of Weifang Medical College, Shandong Province, China
  5. 5Department of Endocrinology, Xinhua Hospital Affiliated to Shanghai Jiaotong University (SJTU) School of Medicine, Shanghai, China
  6. 6Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiaotong University (SJTU) School of Medicine, Shanghai, China
  1. Correspondence to Dr Wei Huang, Department of Genetics, Chinese National Human Genome Center, Bldg. 1, 250 BiBo Road, Shanghai 201203, China; shgc_hw{at}, huangwei{at}


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 (Plogistic regression= 9.52×10−8; PsnpMatrix=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 Plogistic regression=5.53×10−21; combined PsnpMatrix=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.

  • Genetics
  • Genome-wide
  • Complex traits
  • Thyroid disease
  • Endocrinology

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