Functional Connectome-Wide Associations of Schizophrenia Polygenic Risk

Abstract

Schizophrenia is a highly heritable mental disorder characterized by functional dysconnectivity across the brain. However, the relationships between polygenic risk factors and connectome-wide neural mechanisms are unclear. Here, combining genetic and multiparadigm fMRI data of 623 healthy Caucasian adults drawn from the Human Connectome Project, we found that higher schizophrenia polygenic risk scores were significantly correlated with lower functional connectivity in a large-scale brain network primarily encompassing the visual system, default-mode system, and frontoparietal system. Such correlation was robustly observed across multiple fMRI paradigms, suggesting a brain-state-independent neural phenotype underlying individual genetic liability to schizophrenia. Moreover, using an independent clinical dataset acquired from the Consortium for Neuropsychiatric Phenomics, we further demonstrated that the connectivity of the identified network was reduced in patients with schizophrenia and significantly correlated with general cognitive ability. These findings provide the first evidence for connectome-wide associations of schizophrenia polygenic risk at the systems level and suggest that disrupted integration of sensori-cognitive information may be a hallmark of genetic effects on the brain that contributes to the pathogenesis of schizophrenia.