Bivariate Genome-Wide Association Study Implicates ATP6V1G1 as a Novel Pleiotropic Locus Underlying Osteoporosis and Age at Menarche
Bivariate Genome-Wide Association Study Implicates ATP6V1G1 as a Novel Pleiotropic Locus Underlying Osteoporosis and Age at Menarche
复制标题
双变量全基因组关联研究表明 ATP6V1G1 是骨质疏松症和初潮年龄背后的新型多效基因座
DOI：
10.1210/jc.2015-2095
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发表时间：
2015-11-01
影响因子：
5.8
通讯作者：
Deng, Hong-Wen
中科院分区：
文献类型：
--
作者：
Tan, Li-Jun;Wang, Zhuo-Er;Deng, Hong-Wen
目的：初潮年龄（AAM）是由内分泌组织性激素暴露水平的总持续时间决定的。骨质疏松症是最常见的代谢性骨疾病，其主要特征是骨矿物质密度（BMD）降低和低创伤性骨折风险增加。骨是调节性类固醇激素合成和分泌的内分泌器官。骨和性腺之间的相互依赖性强调了遗传方法的重要性，以确定新的多效性遗传因子共同调节BMD和AAM。在这项研究中，我们进行了双变量全基因组关联研究（GWAS），以探索新的种族共同位点和/或基因，可能会影响AAM和BMD.Methods：我们分析了826个无关的中国受试者使用全基因组人类基因分型阵列的基因分型数据。质量控制后，共702 413单核苷酸多态性（SNPs）的关联性进行了测试，使用双变量线性回归模型。有趣的SNPs在三个独立的队列中重复，包括1728名无关的高加索人，709名非洲裔美国人和408名西班牙裔美国人。我们发现了四个SNP（rs 10817638、rs7851259、rs 10982287和rs 4979427），位于ATP 6V 1G 1基因上游，与髋关节BMD-AAM呈双变量相关（分别为P = 4.90 x 10（-7）、P = 1.07 x 10（-6）、P = 1.28 x 10（-5）和P = 5.42 x 10（-5））。这四个SNP在非裔美国人中重复，相应值分别为P = 1.95 x 10（-2）、P = 3.18 x 10（-2）、P = 2.57 x 10（-2）和P = 3.64 x 10（-2）。rs 10817638和rs 10982287在白人（分别为P = 1.76 x 10（-2）和P = 9.42 x 10（-3））和西班牙裔美国人（分别为P = 8.37 x 10（-3）和P = 1.52 x 10（-3））中进一步复制。Meta分析显示rs 10817638和rs 10982287具有更强的关联信号，组合值分别为P = 3.02 × 10（-9）和P = 3.49 × 10（-9）。这些发现增强了我们对BMD和AAM之间遗传关联的认识，并为随后对这些相关基因在疾病/性状（如骨质疏松症和AAM）的病理生理学中的功能研究提供了理论基础。
Objective: Age at menarche (AAM) is determined by the overall duration of endocrine-tissue sex hormone exposure levels. Osteoporosis, the most common metabolic bone disease, is characterized primarily by reduced bone mineral density (BMD) and an increased risk of low trauma fractures. Bone was an endocrine organ regulating the synthesis and secretion of sex steroid hormones. The mutual dependence between bone and gonads underscore the importance of genetic approaches to identify novel pleiotropic genetic factors coregulating BMD and AAM. In this study, we performed a bivariate genome-wide association study (GWAS) to explore novel ethnic common loci and/or genes that may influence both AAM and BMD.Methods: We analyzed genotyping data available for 826 unrelated Chinese subjects using genome-wide human genotyping arrays. After quality control, a total of 702 413 single-nucleotide polymorphisms (SNPs) were tested for association using a bivariate linear regression model. The interesting SNPs were replicated in three independent cohorts including 1728 unrelated Caucasians, 709 African-Americans, and 408 Hispanic-Americans.Results: We found four SNPs (rs10817638, rs7851259, rs10982287, and rs4979427), located upstream of the ATP6V1G1 gene, were bivariately associated with hip BMD-AAM (P = 4.90 x 10(-7), P = 1.07 x 10(-6), P = 1.28 x 10(-5), and P = 5.42 x 10(-5), respectively). These four SNPs were replicated in African-Americans, with corresponding values of P = 1.95 x 10(-2), P = 3.18 x 10(-2), P = 2.57 x 10(-2), and P = 3.64 x 10(-2), respectively. rs10817638 and rs10982287 were further replicated in Caucasians (P = 1.76 x 10(-2) and P = 9.42 x 10(-3), respectively) and Hispanic-Americans (P = 8.37 x 10(-3) and P = 1.52 x 10(-3), respectively). Meta-analyses yielded stronger association signals for rs10817638 and rs10982287 with combined values of P = 3.02 x 10(-9) and P = 3.49 x 10(-9), respectively.Conclusions: Our study implicated ATP6V1G1 as a novel pleiotropic gene underlying variation of both BMD and AAM. The findings enhance our knowledge of genetic associations between BMD and AAM and provide a rationale for subsequent functional studies of these implicated genes in the pathophysiology of diseases/traits, such as osteoporosis and AAM.