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

• Published in: Journal of bone and mineral research 2023-11, Vol.38 (11), p.1635-1644
• Main Authors: Qu, Yang, Xiao, Changfeng, Wu, Xueyao, Zhu, Jingwei, Qin, Chenjiarui, He, Lin, Cui, Huijie, Zhang, Li, Zhang, Wenqiang, Yang, Chunxia, Yao, Yuqin, Li, Jiayuan, Liu, Zhenmi, Zhang, Ben, Wang, Wenzhi, Jiang, Xia
• Format: Article
• Language: English
• Subjects: Body mass index; Bone density; Bone Density - genetics; Bone mineral density; Bone turnover; Female; Genome-wide association studies; Genome-Wide Association Study; Globulins; Humans; Male; Medicin och hälsovetenskap; Mendelian Randomization Analysis; Minerals - metabolism; Osteoporosis; Osteoporosis - genetics; Osteoporosis - metabolism; Phenotype; Risk assessment; Sex Hormone-Binding Globulin - genetics; Sex Hormone-Binding Globulin - metabolism; Sex hormones; Statistical analysis
• ISSN: 0884-0431; 1523-4681; 1523-4681
• DOI: 10.1002/jbmr.4904

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  = -0.11, p = 3.34 × 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 ), with comparable effect sizes observed in both men (beta = -0.16, p = 1.99 × 10 ) and women (beta = -0.19, p = 2.73 × 10 ). 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).