Regional heterogeneity in phenotypic and genetic associations between bone and brain in humans

The co-occurrence of skeletal and neuropsychiatric disorders suggests underlying bone-brain associations, yet their characterization remains limited by the anatomical and biological complexity of both systems. Here, we systematically examine these associations across diverse anatomical locations using structural imaging and genetic data from approximately 45,000 UK Biobank participants. We identify widespread structural associations between bone and brain, with 34.9% of examined pairs showing significant relationships. These associations display pronounced regional heterogeneity, with effect size variation aligning with gradients of cortical development and evolutionary expansion, as well as spatial distributions of GABA and 5HT-1b receptors and gene expression profiles of oligodendrocyte precursor cells and astrocytes. Genetic analyses spanning genome-wide, pathway, locus, and single-variant levels further reveal shared genetic architecture between skeletal and brain structures, as well as with multiple neuropsychiatric and neurological traits. Enrichment within the Wnt signaling pathway highlights a potential mechanistic axis underlying bone-brain coupling, while distinct skeletal regions exhibit differential genetic links to specific brain-related health outcomes. Together, these findings demonstrate that bone-brain associations are pervasive yet exhibit substantial anatomical and genetic heterogeneity, providing a systems-level framework for understanding the shared biology of skeletal and brain health.