Shared genetic architecture between schizophrenia and osteoporosis revealed by multilevel genomic analyses

Schizophrenia is associated with an increased risk of osteoporosis, yet the biological mechanisms underlying this association remain poorly understood. As both disorders are highly polygenic and may share biological pathways, investigating their shared genetic basis could help clarify the mechanisms contributing to their comorbidity. Using summary-level statistics from the largest genome-wide association studies of schizophrenia ( N = 132,644) and six osteoporosis-related phenotypes ( N = 8143–426,824), we comprehensively characterized shared genetic architecture across global, local, and variant levels. Shared loci were subsequently identified and mapped to protein-coding genes, followed by functional enrichment analyses. The analyses revealed varying degrees of polygenic overlap between schizophrenia and osteoporosis-related traits. Significant regional genetic correlations were detected, particularly for femoral neck, forearm, and heel bone mineral density. In total, 195 loci were jointly associated with schizophrenia and osteoporosis-related traits. These loci were mapped to 1376 protein-coding genes, which showed significant enrichment in biological processes related to organonitrogen compound metabolism, anatomical structure development, and biological regulation. Together, these findings provide integrative evidence of genetic overlap between schizophrenia and osteoporosis, highlighting common etiological mechanisms bridging neuropsychiatric and skeletal health, with potential implications for early prevention.