Multivariate Associations Between Structural Brain Networks, Genetics, Environments, and Cognitive-Psychopathological Traits in Children

Abstract

Brain development in childhood is shaped by complex interactions between genetic predispositions, environmental influences, and neural connectivity, yet how these factors jointly contribute to cognitive and mental health outcomes remains unclear. Here, using sparse canonical correlation analysis (SCCA) on data from the Adolescent Brain Cognitive Development (ABCD) Study, the largest longitudinal study of child brain development in the United States (N = 10,246 for environmental and phenotypic analyses; n = 5,724 of European ancestry for polygenic score analyses), we identified robust multivariate associations linking structural brain network properties with polygenic scores (PGS), socioeconomic status (SES) indicators, and cognitive-psychopathological phenotypes. Across all three domains, a consistent topological signature emerged: favorable genetic, environmental, and phenotypic traits were associated with greater nodal efficiency and centrality in temporal-parietal cortical networks, while being inversely associated with nodal connectivity strength in subcortical-limbic regions. Notably, this pattern was observed at the regional rather than the global network level. Mediation analyses further indicated that structural brain network properties partially mediate the influence of genetic and environmental factors on cognitive-psychopathological outcomes, accounting for approximately 5.6% and 3.9% of the total effects within the genetic and environmental pathways, respectively. These findings, with the SCCA associations replicated across held-out test and site-based external validation sets, provide empirical support for a multivariate, systems-level perspective on neurodevelopment, highlighting structural brain network organization as a potential biological pathway through which genetic liability and modifiable environmental conditions relate to cognitive and mental health outcomes in late childhood.