Shared genetic architecture of gray matter deficits in schizophrenia and bipolar disorder: evidence from structural neuroimaging-genetic analyses.

BACKGROUND

Schizophrenia (SCZ) and bipolar disorder (BD) share substantial clinical and neuroanatomical features, yet the neurogenetic basis underlying their shared gray matter volume (GMV) deficits remains poorly understood.

METHODS

We conducted meta-analyses to identify convergent GMV alterations across the two disorders. Genome-wide association studies (GWAS) were performed to uncover genetic variants associated with the shared GMV deficits region in UK Biobank participants. Polygenic risk score (PRS)-GMV associations were analyzed to examine the cumulative influence of genetic risk on GMV in regions with shared deficits. Furthermore, pleiotropic SNPs jointly associated with SCZ, BD, and shared GMV deficits were identified. Spatiotemporal gene expression profiling was utilized to characterize the developmental trajectories, and molecular docking was performed to explore potential drugs.

RESULTS

Meta-analysis revealed consistent overlapping GMV reductions in frontal, temporal, and insular regions across SCZ and BD, based on 6,620 patients and 7,762 controls. GWAS identified 14 SNPs associated with the shared GMV deficits. PRS analyses showed that modestly higher SCZ polygenic risk correlated with decreased GMV of shared regions. Two pleiotropic SNPs - rs11191368 and rs79668541 - were linked to both disorders and the shared GMV deficits. Spatiotemporal expression analyses demonstrated distinct developmental trajectories, and molecular docking highlighted 168 drugs with binding interactions for shared genes.

CONCLUSIONS

This study delineates shared neurogenetic mechanisms linking GMV abnormalities to genetic risk across SCZ and BD. Given the cross-sectional design, future longitudinal studies in independent cohorts are warranted to validate these findings and clarify the temporal relationships.