Lifestyle and Transcriptional Signatures Associated with Ethnicity/Race-Related Variations in the Functional Connectome

Understanding the variation of functional architecture across individuals and populations is fundamental to advancing our knowledge of human health and behavior. Yet, while functional organization differences related to ethnicity/race are consistently reported, their underlying mechanisms remain poorly understood. Here, we apply precision individualized functional mapping to systematically investigate ethnicity/race-related differences between African American (AA) and white American (WA) cohorts in the brain’s intrinsic organization and their associations with lifestyle and transcriptional signatures. We show that variations in network topography and functional connectivity across these ethnic/racial groups follow a hierarchical sensorimotor–association axis and are constrained by brain morphology. Importantly, we identify lifestyle factors—particularly education and substance use—that significantly mediate these associations between ethnicity/race and functional connectivity. Leveraging human brain gene expression data, we further demonstrate that cortical transcriptional patterns are spatially aligned with ethnicity/race-related variability in functional connectivity. Gene ontology analyses of associated genes reveal significant enrichment in biological processes such as synaptic signaling and neuronal system development. Together, these findings uncover a multi-layered framework linking ethnicity/ race-related differences in brain function to structural constraints, lifestyle influences, and molecular signatures, and point to the need for a more comprehensive and equitable understanding of human brain diversity.