The Mediating Role of Structural Connectivity in Genetic Effects on Functional Brain Networks

Understanding the complex relationships among genetic variations, brain structural anatomy, and functional alterations is a fundamental yet challenging task in neuroimaging genetics. In this study, we employ a causal mediation framework under structural modeling to systematically investigate the mediating role of interand intra-network structural connectivity (SC) in linking whole-genome single nucleotide polymorphisms (SNPs) to brain functional connectivity (FC) across both resting-state and task-based conditions during neurodevelopment. Utilizing baseline and follow-up SC and FC network traits along with ∼500k SNPs along the genome from 11,666 unique subjects under the Adolescent Brain Cognitive Development (ABCD) study, we first conduct genome-wide association studies (GWAS) to identify candidate SNPs associated with structural and functional network traits. Subsequently, mediation analyses reveal key genetic exposures that directly influence brain functional networks and indirectly impact FC through SC network mediators. These results provide deeper insights into how genetic variations shape brain structural and functional network organizations, along with revealing the influence of brain anatomical topologies on functional fingerprints. This work enhances the understanding of the causal effect pathways among genetic factors and large-scale brain structural and functional networks, advancing our understanding of the genetic underpinnings of neurodevelopmental processes.