Genetically informed dissection of multimodal brain aging and ten major psychiatric disorders

Brain age gap (BAG), defined as the deviation between neuroimaging-predicted brain age and chronological age, has emerged as an imaging-derived phenotype associated with psychiatric disorders. Although both BAG and psychiatric disorders are highly heritable, their shared genetic architecture has remained poorly understood. Here, we integrated large-scale genome-wide association study (GWAS) summary statistics for multimodal BAG phenotypes derived from UK Biobank neuroimaging data, together with GWAS data for ten major psychiatric disorders from the Psychiatric Genomics Consortium and FinnGen, to systematically investigate their shared genetic architecture. We identified significant genetic correlations across seven BAG-disorder pairs and quantified widespread polygenic overlap (maximum Dice coefficient = 58.3%). Across 98 genomic loci jointly associated with BAG phenotypes and psychiatric traits, the majority of variants mapped to putative regulatory regions. Gene mapping uncovered a substantial number of genes contributing to multiple disorders, highlighting extensive cross-disorder genetic sharing. These genes were enriched in pathways related to synaptic signaling, neuronal development, and mitochondrial function-key neurobiological processes involved in both brain aging and psychiatric pathology. Bidirectional Mendelian randomization analyses provided no robust evidence for causal relationships between BAG phenotypes and psychiatric disorders. Collectively, our findings reveal partial genetic overlap between altered brain aging and diverse psychiatric disorders, providing an integrative cross-modality perspective on the shared genetic influences and related biological pathways linking brain aging and psychiatric vulnerability.