TY - JOUR T1 - An X chromosome-wide association analysis identifies variants in <em>GPR174</em> as a risk factor for Graves’ disease JF - Journal of Medical Genetics JO - J Med Genet SP - 479 LP - 485 DO - 10.1136/jmedgenet-2013-101595 VL - 50 IS - 7 AU - Xun Chu AU - Min Shen AU - Fang Xie AU - Xiao-Jing Miao AU - Wei-Hua Shou AU - Lin Liu AU - Peng-Peng Yang AU - Ya-Nan Bai AU - Kai-Yue Zhang AU - Lin Yang AU - Qi Hua AU - Wen-Dong Liu AU - Yan Dong AU - Hai-Feng Wang AU - Jin-Xiu Shi AU - Yi Wang AU - Huai-Dong Song AU - Sai-Juan Chen AU - Zhu Chen AU - Wei Huang Y1 - 2013/07/01 UR - http://jmg.bmj.com/content/50/7/479.abstract N2 - 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. ER -