CONTEXT: Despite the well-established regulatory role of vitamin D in maintaining bone health, little is known about the shared genetics and causality of the association between serum 25-hydroxyvitamin D (25OHD) and bone mineral density (BMD). OBJECTIVE: We aimed to investigate the shared genetic architecture and causal relationship between serum 25OHD and BMD, providing insights into their underlying biological mechanisms. METHODS: Leveraging individual-level data from the UK Biobank (UKB) cohort and summary-level data from the genome-wide association studies (GWASs) conducted on European individuals for serum 25OHD (N = 417 580) and estimated heel BMD (eBMD, N = 426 824), we systematically elucidated the shared genetic architecture underlying serum 25OHD and eBMD through a comprehensive genome-wide cross-trait design. RESULTS: Despite a lack of global genetic correlation (rg=-0.002
P = .95), a statistically significant local signal was discovered at 5p11-5q11.9. Two-sample mendelian randomization (MR) indicated no causal association in the overall population (β=.003, 95% CI, -0.04 to 0.03
P = .93), while positive causal effects were observed in males (β=.005, 95% CI, 0.00 to 0.01
P = .03) and older individuals (β=.009, 95% CI, 0.00∼0.02
P = .01) according to one-sample MR. A total of 49 pleiotropic single-nucleotide variations (SNVs), with 4 novel SNVs (rs1077151, rs79873740, rs12150353, and rs4760401), were identified, and a total of 95 gene-tissue pairs exhibited overlap, predominantly enriched in the nervous, digestive, exocrine/endocrine, and cardiovascular systems. Protein-protein interaction analysis identified RPS9 and RPL7A as hub genes. CONCLUSION: This study illuminates the potential health benefits of enhancing serum 25OHD levels to mitigate the risk of osteoporosis among men and individuals older than 65 years. It also unveils a shared genetic basis between serum 25OHD and eBMD, offering valuable insights into the intricate biological pathways.