An X chromosome-wide association analysis identifies variants in GPR174 as a risk factor for Graves' disease.
An X chromosome-wide association analysis identifies variants in GPR174 as a risk factor for Graves' disease.
复制标题
DOI：
10.1136/jmedgenet-2013-101595
复制
发表时间：
2013-07
影响因子：
4
通讯作者：
Huang W
中科院分区：
文献类型：
--
作者：
Chu X;Shen M;Xie F;Miao XJ;Shou WH;Liu L;Yang PP;Bai YN;Zhang KY;Yang L;Hua Q;Liu WD;Dong Y;Wang HF;Shi JX;Wang Y;Song HD;Chen SJ;Chen Z;Huang W
格雷夫斯病是一种女性占优势的自身免疫性疾病，X染色体对其风险的贡献长期以来一直受到重视。然而，没有X连锁易感基因座已被确定从最近的全基因组关联研究（GWAS）。我们重新检查了我们最近的GWAS的X染色体数据，包括以前从X染色体分析中排除的男性。使用逻辑回归分析（包括性别作为协变量）和在snpMatrix中实施的假设X染色体失活的加法方法分析数据。在Xq21.1处发现了一簇单核苷酸多态性（SNP），显示出与全基因组显著性相关，其中rs3827440是GPR 174的非同义SNP（Plogistic回归= 9.52×10−8; PsnpMatrix=4.60×10−9; OR=1.76，95%CI 1.45至2.13）。在一个独立的样本收集集中重现了这种关联，该样本收集集包括4564例Graves病病例和3968例性别匹配的对照（组合的Plogistic回归=5.53×10−21;组合的PsnpMatrix=4.26×10−22; OR=1.69，95%CI 1.53至1.86）。值得注意的是，GPR 174在免疫相关组织中广泛表达，并且rs3827440基因型与不同的mRNA水平相关（p=0.002）。在我们的表达分析中，GPR 174没有显示性别偏好的基因表达。重测序研究表明，GPR 174基因区域中的一些罕见变异对疾病风险的贡献为1.16×10−3。Graves病X连锁危险基因座的发现扩展了我们对X染色体在疾病易感性中作用的理解。
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). 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. 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. The finding of an X-linked risk locus for Graves’ disease expands our understanding of the role of the X chromosome in disease susceptibility.
登录
查看更多内容
影响因子：
30.8
作者：
Stephens, M;Sloan, JS;Nickerson, DA
通讯作者：
Nickerson, DA
影响因子：
9.8
作者：
Li, Bingshan;Leal, Suzanne M.
通讯作者：
Leal, Suzanne M.
一项全基因组关联研究确定了格雷夫斯病的两个新风险位点
影响因子：
30.8
作者：
Chu, Xun;Pan, Chun-Ming;Song, Huai-Dong
通讯作者：
Song, Huai-Dong
DOI：
10.1016/j.bbrc.2012.11.046
发表时间：
2013-01-04
影响因子：
3.1
作者：
Sugita, Kazuya;Yamamura, Chiaki;Fujita, Norihisa
通讯作者：
Fujita, Norihisa
影响因子：
3.2
作者：
Elsheikh, M;Wass, JAH;Conway, GS
通讯作者：
Conway, GS