Although the impact of sex hormones on bone metabolism is well-documented, effect of their primary modulator, sex hormone-binding globulin (SHBG), remains inconclusive. This study aims to elucidate the genetic overlap between SHBG and heel estimated bone mineral density (eBMD), a widely-accepted tool for osteoporosis management and fracture risk assessment. Using summary statistics from large-scale genomewide association studies conducted for SHBG (N = 370,125), SHBG adjusted for body mass index (SHBGa, N = 368,929), and eBMD (N = 426,824), a comprehensive genomewide cross-trait approach was performed to quantify global and local genetic correlations, identify pleiotropic loci, and infer causal associations. A significant overall inverse genetic correlation was found for SHBG and eBMD (r_g = −0.11, p = 3.34 × 10⁻¹⁰), which was further supported by the significant local genetic correlations observed in 11 genomic regions. Cross-trait meta-analysis revealed 219 shared loci, of which seven were novel. Notably, four novel loci (rs6542680, rs8178616, rs147110934, and rs815625) were further demonstrated to colocalize. Mendelian randomization identified a robust causal effect of SHBG on eBMD (beta = −0.22, p = 3.04 × 10⁻¹³), with comparable effect sizes observed in both men (beta = −0.16, p = 1.99 × 10⁻⁶) and women (beta = −0.19, p = 2.73 × 10⁻⁹). Replacing SHBG with SHBGa, the observed genetic correlations, pleiotropic loci and causal associations did not change substantially. Our work reveals a shared genetic basis between SHBG and eBMD, substantiated by multiple pleiotropic loci and a robust causal relationship. Although SHBG has been implicated in preventing and screening aging-related diseases, our findings support its etiological role in osteoporosis. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

中文翻译：

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性激素结合球蛋白与骨矿物质密度之间的遗传相关性、共享位点和因果关系：来自大规模全基因组跨性状分析的见解

尽管性激素对骨代谢的影响已有充分记录，但其主要调节剂性激素结合球蛋白 (SHBG) 的作用仍无定论。本研究旨在阐明性激素结合球蛋白 (SHBG) 和足跟估计骨矿物质密度 (eBMD) 之间的遗传重叠，eBMD 是一种广泛接受的骨质疏松症管理和骨折风险评估工具。利用对 SHBG ( N  = 370,125)、根据体重指数调整的 SHBG (SHBGa, N  = 368,929) 和 eBMD ( N = 426,824)进行的大规模全基因组关联研究的汇总统计数据 ，进行了全面的全基因组跨性状方法量化全局和局部遗传相关性，识别多效性基因座，并推断因果关系。SHBG 和 eBMD 发现显着的整体逆遗传相关性（r _g  = -0.11，p  = 3.34 × 10 ^-10），在 11 个基因组区域中观察到的显着局部遗传相关性进一步支持了这一点。跨性状荟萃分析揭示了 219 个共享基因座，其中 7 个是新颖的。值得注意的是，四个新基因座（rs6542680、rs8178616、rs147110934 和 rs815625）被进一步证明是共定位的。孟德尔随机化确定了性激素结合球蛋白 (SHBG) 对 eBMD 的强大因果效应 (beta = -0.22, p  = 3.04 × 10 ^-13 )，在男性 (beta = -0.16, p  = 1.99 × 10 ^-6 ) 和女性中观察到的效应大小相当（β = -0.19，p  = 2.73 × 10 ^-9）。用SHBGa代替SHBG，观察到的遗传相关性、多效性位点和因果关联没有显着变化。我们的工作揭示了性激素结合球蛋白 (SHBG) 和 eBMD 之间的共同遗传基础，并通过多个多效性基因座和强有力的因果关系得到证实。尽管性激素结合球蛋白（SHBG）与预防和筛查衰老相关疾病有关，但我们的研究结果支持其在骨质疏松症中的病因学作用。© 2023 作者。《Journal of Bone and Mineral Research》由 Wiley periodicals LLC 代表美国骨与矿物研究学会 (ASBMR) 出版。