Genetic mechanisms underlying the associations between brain structure and mental health

Brain-wide association studies have linked brain structure to complex mental health phenotypes, yet the genetic underpinnings of these effects remain largely unclear. Here, we leverage multimodal neuroimaging, behavioral and genetic data from the UK Biobank to develop an integrative framework combining brain-wide association studies and GWAS to elucidate how genetic variants affect the relationship between brain structure and mental health. Our multivariate brain-wide association study identifies two reproducible brain structural modes: a cerebellar-dominant mode and a cortical-dominant mode that explain individual differences in mental health measures. Using GWAS, we subsequently identify 30 and 15 independent significant variants respectively for each mode, indicating distinct genetic architectures with no signal overlap. Post-GWAS analyses indicate distinct biological pathways: the cerebellar-dominant mode is enriched for genes involved in chromatin organization and epigenetic regulation, while the cortical-dominant mode is linked to neurotransmitter metabolism. Moreover, we identify 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. We validate the framework in the independent HCP cohort, supporting the cross-cohort generalizability of the identified brain–behavior and genetic associations. Brain-wide association studies link brain structure to mental health, but the underlying genetics remain unclear. Here, the authors integrate brain- and genome-wide analyses to identify two brain-mental health modes with distinct genetic architectures.