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.

Fig. 1. Flowchart of the data processing pipeline used in the study.

The connectomic associations were identified in the HCP sample and further investigated for clinical associations in the CNP sample.

Fig. 2. Connectome-wide associations of PRS in the HCP data.

a The identified network consisted of 54 nodes and 69 edges predominantly located in the visual system, default-mode system, and frontoparietal system (SM sensorimotor, VIS visual, AUD auditory, DMN default-mode, CON cingulo-opercular, FPN frontoparietal, SAL salience, ATT attention, SUB subcortex). b The scatter plot showed significant correlation between PRSs and the mean cross-paradigm connectivity of the identified network. Note that the cross-paradigm connectivity values were defined at the PCA space and were rescaled to be mean centered at zero. c The functional connectivity strengths of the identified network were significantly correlated with PRSs in each of the eight studied paradigms, confirming that the observed association is brain-state-independent.

Fig. 3. Clinical and cognitive relevance of the PRS-related network in the CNP data.

a Significant group differences were shown for the mean cross-paradigm connectivity of the identified network, which was particularly driven by the difference between schizophrenia and controls. b Lower connectivity of the identified network was significantly correlated with lower scores for IQ in patients with schizophrenia but not healthy controls. c In patients, significant correlation between network connectivity and IQ was only observed in males but not females. The error bars indicate standard errors.