Genetic Correlation, Shared Loci, and Causal Association Between Sex Hormone ‐Binding Globulin and Bone Mineral Density: Insights From a Large‐Scale Genomewide Cross‐Trait Analysis

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 (rg = −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 pleiotr...

Source: Journal of Bone and Mineral Research - September 14, 2023 Category: Orthopaedics Authors: Yang Qu, Changfeng Xiao, Xueyao Wu, Jingwei Zhu, Chenjiarui Qin, Lin He, Huijie Cui, Li Zhang, Wenqiang Zhang, Chunxia Yang, Yuqin Yao, Jiayuan Li, Zhenmi Liu, Ben Zhang, Wenzhi Wang, Xia Jiang Tags: Research Article Source Type: research