Genetic, transcriptomic, metabolic, and neuropsychiatric underpinnings of cortical functional gradients

Functional gradients capture the organization of functional activity in the cerebral cortex, delineating transitions from sensory to higher-order association areas. While group-level gradient patterns are well-characterized, the biological mechanisms underlying individual variability remain poorly understood. Here, we integrate genetic, transcriptomic, and metabolic data across large-scale cohorts to investigate the biological basis of functional gradients and their relevance to neuropsychiatric conditions. Using twin-based heritability analyses and genome-wide association studies (GWAS) in over 30,000 individuals based on three datasets, we identified consistent heritability patterns and five genetic loci associated with gradient organization. These loci are linked to sixteen genes involved in metabolic pathways, with gene expression patterns spatially correlating with functional gradients. Furthermore, we observed significant associations between cardiovascular metabolic biomarkers and gradient architecture. Polygenic risk scores for neuropsychiatric conditions, including schizophrenia, bipolar disorder, and post-traumatic stress disorder, were significantly associated with gradient loadings, suggesting shared genetic influences on functional organization and mental health risk. Our findings highlight a complex interplay between genetic variation, metabolic processes, and brain function, offering new insights into the biological foundations of functional brain organization and its implications for neuropsychiatric vulnerability.