Abstract
BACKGROUND: The pattern of abnormal resting-state brain function has been documented in schizophrenia (SCZ). However, as of yet, it remains unclear whether this pattern is of genetic predisposition or related to the illness itself. METHODS: A systematical meta-analysis was performed to identify resting-state functional differences in probands and their high-risk first-degree relatives of schizophrenia (FDRs-SCZ) using Seed-based d Mapping software. Subsequently, spatial associations between postmortem gene expression and neurotransmitters distribution data and neural activity alterations were conducted to uncover neural mechanisms underlaying FDRs-SCZ and SCZ from a multidimensional perspective. RESULTS: A total of 13 studies comprising 503 FDRs-SCZ and 605 healthy controls (HCs) and 129 studies comprising 6506 patients with SCZ and 6982 HCs were included. Compared to HCs, FDRs-SCZ displayed increased spontaneous functional activity in the bilateral anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC); patients with SCZ showed decreased spontaneous functional activity in the bilateral ACC/mPFC, bilateral postcentral gyrus, and right middle temporal gyrus as well as increased spontaneous functional activity in the bilateral striatum. The altered functional activity in FDRs-SCZ and SCZ shared similar spatial associations with genes enriched in potassium ion transmembrane transport, channel activity, and complex. The FDRs-SCZ and SCZ-related brain functional patterns were additionally associated with dopaminergic, serotonergic, and cholinergic neurotransmitter distribution. CONCLUSIONS: SCZ-related resting-state functional, neuroimaging transcriptomes, and neurotransmitters abnormalities may exist in high-risk unaffected FDRs-SCZ, rather than just in overt SCZ. The study extended the evidence that altered brain function, along with their spatial correlations to genetics and neurotransmitter systems, may associate with genetic vulnerability for SCZ.