Genetic mechanisms underlying the associations between brain structure and mental health

Brain-wide association studies (BWAS) have linked brain structure to complex mental health phenotypes, yet the genetic underpinnings of these BWAS effects remain unknown. Leveraging multimodal neuroimaging, behavioral and genetic data from UK Biobank, we developed an integrative framework combining BWAS and genome-wide association studies (GWAS) to elucidate how genetic variants affect the relationship between brain structure and mental health. Our multivariate BWAS identified two reproducible brain structural modes: a cerebellar-dominant mode and a cortical-dominant mode that explain individual differences in mental health measures. Subsequent GWAS identified 30 and 15 independent significant variants for the two modes, respectively, indicating distinct genetic architectures with no signal overlap. Post-GWAS analyses further revealed distinct biological pathways: genes related to the cerebellar-dominant mode was enriched for gene sets involved in chromatin organization and epigenetic regulation, whereas the cortical-dominant mode was linked to neurotransmitter metabolism. Moreover, we identified shared genetic influences between the brain modes and both mental health and cognitive traits, as well as causal effects of the brain modes on these outcomes. Collectively, our study illuminate how genetic variants contributes to psychological vulnerability through specific neuroanatomical patterns, providing a unified framework for interpreting BWAS in a genetic context.