Aim: To investigate whether large-scale brain imaging-derived phenotypes share genetic architecture with osteoporosis and to evaluate potential pleiotropic loci and candidate mediators linking brain structure and skeletal risk.

Methods: We analyzed summary statistics for 3,935 UK Biobank brain imaging-derived phenotypes (IDPs) and a meta-analyzed European osteoporosis genome-wide association studies (GWAS) using generalized and inverse-variance-weighted Mendelian randomization. Five bone mineral density datasets were used for validation. Linkage disequilibrium score regression, pleiotropy analysis under the composite null hypothesis, colocalization, and two-step Mendelian randomization were applied to characterize shared loci and to assess candidate mediation.

Results: Seventy-five imaging-derived phenotypes showed evidence of association with osteoporosis, and 16 remained supported after validation with bone mineral density traits. BrainSegVol-to-eTIV (estimated total intracranial volume) and left thalamic volume CL (central lateral nucleus) showed the most consistent signals across osteoporosis and bone mineral density outcomes. Seven imaging-derived phenotypes showed significant genetic correlation with osteoporosis by linkage disequilibrium score regression. Forty pleiotropic loci were detected at genome-wide significance, and six had colocalization support. HLA-DRB1 (human leukocyte antigen - DRB1) showed evidence consistent with partial mediation of the association between BrainSegVol-to-eTIV and osteoporosis, with an estimated mediation proportion of 41.8% and a 95% confidence interval of 19.90% to 63.70%.

Conclusion: Genome-wide cross-trait analyses support shared genetic architecture between selected imaging-derived phenotypes and osteoporosis. BrainSegVol-to-eTIV, left thalamic volume CL, and HLA-DRB1 emerged as prioritized statistical signals, although replication and functional validation remain necessary before any mechanistic brain-bone pathway can be inferred.

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