In this study, we aimed to investigate the causal associations of brain structure with bone mineral density (BMD). Based on the genome-wide association study (GWAS) summary statistics of 1 325 brain imaging-derived phenotypes (BIDPs) of brain structure from the UK Biobank and GWAS summary datasets of 5 BMD locations, including the total body, femoral neck, lumbar spine, forearm, and heel from the GEFOS Consortium, linkage disequilibrium score regression (LDSC) was conducted to determine the genetic correlations, and Mendelian randomization (MR) was then performed to explore the causal relationship between the BIDPs and BMD. Several sensitivity analyses were performed to verify the strength and stability of the present MR outcomes. To increase confidence in our findings, we also performed confirmatory MR between BIDPs and osteoporosis. LDSC revealed that 1.93% of BIDPs, with a false discovery rate (FDR) < 0.01, were genetically correlated with BMD. Additionally, we observed that 1.31% of BIDPs exhibited a significant causal relationship with BMD (FDR < 0.01) through MR. Both the LDSC and MR results demonstrated that the BIDPs “Volume of normalized brain,” “Volume of gray matter in Left Inferior Frontal Gyrus, pars opercularis,” “Volume of Estimated Total Intra Cranial” and “Volume-ratio of brain segmentation/estimated total intracranial” had strong associations with BMD. Interestingly, our results showed that more left BIDPs were causally associated with BMD, especially within and around the left frontal region. In conclusion, a part of the brain structure causally influences BMD, which may provide important perspectives for the prevention of osteoporosis and offer valuable insights for further research on the brain-bone axis.

在这项研究中，我们旨在调查大脑结构与骨矿物质密度（BMD）的因果关系。基于英国生物银行1 325个脑结构的全基因组关联研究（GWAS）汇总统计和5个BMD位置的GWAS汇总数据集，包括全身、股骨颈、腰椎对来自 GEFOS 联盟的前臂和足跟进行连锁不平衡评分回归 (LDSC) 以确定遗传相关性，然后进行孟德尔随机化 (MR) 来探索 BIDP 与 BMD 之间的因果关系。进行了多项敏感性分析来验证当前 MR 结果的强度和稳定性。为了增加对我们研究结果的信心，我们还在 BIDP 和骨质疏松症之间进行了验证性 MR。LDSC 显示，1.93% 的 BIDP 与 BMD 存在遗传相关性，错误发现率 (FDR) < 0.01。此外，我们通过 MR 观察到 1.31% 的 BIDP 与 BMD 表现出显着的因果关系（FDR < 0.01）。LDSC 和 MR 结果均表明 BIDP“标准化大脑体积”、“左额下回、盖部灰质体积”、“估计颅内总体积”和“大脑分割/估计的体积比” “全颅内”与 BMD 有很强的相关性。有趣的是，我们的结果表明，更多的左侧 BIDP 与 BMD 存在因果关系，尤其是在左额叶区域内和周围。总之，大脑结构的一部分对骨密度有因果影响，这可能为预防骨质疏松症提供重要视角，并为脑骨轴的进一步研究提供有价值的见解。