Sex-Modulated Coupling Between Genetically-Regulated Gene Expression and Functional Network Connectivity in Schizophrenia

Schizophrenia is associated with distributed genetic, molecular, and functional brain network abnormalities, where sex differences have been well documented. However, whether sex difference exists in genetically regulated molecular variation, and how sex impacts the relationship between regulatory liability and large-scale functional dysconnectivity in schizophrenia, remain largely unclear. Here, we integrated brain eQTL-predicted gene-expression features with resting-state functional network connectivity (FNC) using an independent multimodal decomposition framework. In 367 participants from FBIRN and COBRE, gene-expression and FNC features were independently decomposed into latent components and screened for sex differences and schizophrenia associations. We identified a schizophrenia-associated gene-expression component that also showed a significant sex difference and was enriched in cerebellar tissues and biological processes related to vesicle and membrane organization and intracellular trafficking. This gene-expression component was significantly associated with a schizophrenia-associated FNC component involving cortical, subcortical, and cerebellar systems. Particularly, the gene-expression and FNC components also presented a significant sex-by-gene interaction characterized by a stronger negative association in males and a weaker positive association in females. In UK Biobank, the schizophrenia-associated gene-expression effect replicated in 2,273 individuals with schizophrenia and matched controls, while the multimodal association and its sex-dependent interaction also replicated in 4,206 participants with matched genetic and imaging data. These findings suggest that schizophrenia-related regulatory and functional-network abnormalities may converge across biological scales and that their coupling may be moderated by sex.