Tan Li-Jun, Wang Zhuo-Er, Wu Ke-Hao, Chen Xiang-Ding, Zhu Hu, Lu Shan, Tian Qing, Liu Xiao-Gang, Papasian Christopher J, Deng Hong-Wen
Laboratory of Molecular and Statistical Genetics (L.-J.T., Z.-E.W., K.-H.W., X.-D.C., H.Z., S.L., H.-W.D.), College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China; Center of Bioinformatics and Genomics (Q.T., H.-W.D.), School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana 70112; School of Life Science and Technology (X.-G.L.), Xi'an Jiaotong University, Xi'an, Shanxi, People's Republic of China; and Department of Basic Medical Science (C.J.P.), School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108.
J Clin Endocrinol Metab. 2015 Nov;100(11):E1457-66. doi: 10.1210/jc.2015-2095. Epub 2015 Aug 27.
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.
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.
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 × 10(-7), P = 1.07 × 10(-6), P = 1.28 × 10(-5), and P = 5.42 × 10(-5), respectively). These four SNPs were replicated in African-Americans, with corresponding values of P = 1.95 × 10(-2), P = 3.18 × 10(-2), P = 2.57 × 10(-2), and P = 3.64 × 10(-2), respectively. rs10817638 and rs10982287 were further replicated in Caucasians (P = 1.76 × 10(-2) and P = 9.42 × 10(-3), respectively) and Hispanic-Americans (P = 8.37 × 10(-3) and P = 1.52 × 10(-3), respectively). Meta-analyses yielded stronger association signals for rs10817638 and rs10982287 with combined values of P = 3.02 × 10(-9) and P = 3.49 × 10(-9), respectively.
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.
初潮年龄（AAM）由内分泌组织性激素暴露水平的总体持续时间决定。骨质疏松症是最常见的代谢性骨病，其主要特征是骨矿物质密度（BMD）降低以及低创伤性骨折风险增加。骨骼是调节性类固醇激素合成与分泌的内分泌器官。骨骼与性腺之间的相互依存关系凸显了采用遗传学方法来识别共同调节骨密度和初潮年龄的新型多效性遗传因素的重要性。在本研究中，我们开展了一项双变量全基因组关联研究（GWAS），以探索可能同时影响初潮年龄和骨密度的新型种族常见基因座和/或基因。
我们使用全基因组人类基因分型芯片分析了826名无亲缘关系的中国受试者的基因分型数据。经过质量控制后，共使用双变量线性回归模型对702413个单核苷酸多态性（SNP）进行了关联测试。这些有趣的SNP在三个独立队列中进行了重复验证，包括1728名无亲缘关系的白种人、709名非裔美国人以及408名西班牙裔美国人。
我们发现位于ATP6V1G1基因上游的四个SNP（rs10817638、rs7851259、rs10982287和rs4979427）与髋部骨密度 - 初潮年龄呈双变量关联（P值分别为4.90×10⁻⁷、1.07×10⁻⁶、1.28×10⁻⁵和5.42×10⁻⁵）。这四个SNP在非裔美国人中得到了重复验证，相应的P值分别为1.95×10⁻²、3.18×10⁻²、2.57×10⁻²和3.64×10⁻²。rs10817638和rs10982287在白种人（P值分别为1.76×10⁻²和9.42×10⁻³）以及西班牙裔美国人（P值分别为8.37×10⁻³和1.52×10⁻³）中进一步得到了重复验证。荟萃分析得出rs10817638和rs10982287的关联信号更强，合并后的P值分别为3.02×10⁻⁹和3.49×10⁻⁹。
我们的研究表明ATP6V1G1是一个新的多效性基因，是骨密度和初潮年龄变异的基础。这些发现增进了我们对骨密度和初潮年龄之间遗传关联的认识，并为后续对这些相关基因在骨质疏松症和初潮年龄等疾病/性状病理生理学中的功能研究提供了理论依据。
