Shared genetic and environmental influences on altered functional connectivity and schizophrenia liability

Schizophrenia is characterised by dysconnectivity of several resting-state functional brain networks, potentially reflecting reduced efficiency of brain communication. It remains unclear to what extent dysconnectivity is influenced by genetic or environmental liabilities to develop the disease. This study investigated whether such dysconnectivity indicates genetic liability or environmental risk of schizophrenia and its relation to cognitive functioning. Resting-state fMRI at 3T was measured in 71 individual twins discordant for schizophrenia and 154 individual matched healthy control twins. Functional connectivity was calculated within and between eight cortical networks and seven subcortical regions. Structural equation modelling assessed the heritability of connectivity, and its phenotypic, genetic, shared environmental and unique environmental associations with schizophrenia liability, as well as its relation to cognitive functioning. Phenotypic associations with increased schizophrenia liability were found in 12 connections (11%), with 8 showing hyperconnectivity and 4 hypo-connectivity. Two connections were partly explained by genetic overlap between disease liability and connectivity, i.e., hyperconnectivity of the sensorimotor-thalamic connection; hypoconnectivity of the sensorimotor-hippocampal connection. Five connections were partly explained by unique environmental overlap with schizophrenia liability, i.e., hyperconnectivity of the dorsal attention-thalamic, visual-thalamic and amygdala-accumbens connections; hypoconnectivity of the sensorimotor-hippocampal and default mode-salience connections. Increased hyperconnectivity was associated with lower cognitive functioning in this cohort enriched for schizophrenia. Dysconnectivity between functional brain networks is present with increased schizophrenia liability, with both hyper- and hypo-connectivity due to genetic and unique environmental influences. Hyperconnectivity between networks is related to lower cognitive functioning and may constitute a genetic or environmental marker for increased schizophrenia liability.