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Schizophrenia (SCZ) is a serious and complex mental disorder with high heritability. Polygenic risk score (PRS) is a useful tool calculating the accumulating effects of multiple common genetic variants of schizophrenia. The amplitude of low-frequency fluctuation (ALFF) is an efficient index to reflect spontaneous, intrinsic neuronal activity. Aberrant ALFF of brain regions were reported in schizophrenia frequently, but the relationship between PRS and ALFF has not been studied. In the present study, we compared PRS and ALFF in 101 schizophrenia patients and 106 age-matched healthy controls to test their associations with schizophrenia. Then, the correlation of PRS with ALFF was measured to reveal the effect of polygenic risk on brain activity in schizophrenia. We found that schizophrenia patients showed significant differences in PRS and ALFF compared with controls. Twenty-six brain regions showed significant difference of ALFF between schizophrenia cases and controls, of which left inferior frontal gyrus, triangular part (IFGtriang.L) showed increased activity in schizophrenia. PRS-SCZ was positively correlated with ALFF in IFGtriang.L in 57 non-chronic patients. Genes involved in synaptic organization and transmission, especially in glutamatergic synapse, were highly enriched in PRS-SCZ genes, suggesting the dysfunction of synapses in schizophrenia. These results help to understand the molecular mechanism underlying schizophrenia and related brain dysfunction., (Copyright © 2021. Published by Elsevier Ltd.)

Although the diagnoses based on phenomenology have many practical advantages, accumulating evidence shows that schizophrenia and autism spectrum disorder (ASD) share some overlap in genetics and clinical presentation. It remains largely unknown how ASD-associated polygenetic risk contributes to the pathogenesis of schizophrenia. In the present study, we calculated high-resolution ASD polygenic risk scores (ASD PRSs) and selected optimal ten ASD PRS with minimal P values in the association analysis of PRSs, with schizophrenia to assess the effect of ASD PRS on brain neural activity in schizophrenia cases and controls. We found that amplitude of low-frequency fluctuation in left amygdala was positively associated with ASD PRSs in our cohort. Correlation analysis of ASD PRSs with facial emotion recognition test identified the negative correlation of ASD PRSs with negative emotions in schizophrenia cases and controls. Finally, functional enrichment analysis of PRS genes revealed that neural system function and development, as well as signal transduction, were mainly enriched in PRS genes. Our results provide empirical evidence that polygenic risk for ASD contributes to schizophrenia by the intermediate phenotypes of left amygdala function and emotion recognition. It provides a promising strategy to understand the relationship between phenotypes and genotypes shared in mental disorders.

Analysis linking directly genomics, neuroimaging phenotypes and clinical measurements is crucial for understanding psychiatric disorders, but remains rare. Here, we describe a multi-scale analysis using genome-wide SNPs, gene expression, grey matter volume (GMV), and the positive and negative syndrome scale scores (PANSS) to explore the etiology of schizophrenia. With 72 drug-naive schizophrenic first episode patients (FEPs) and 73 matched heathy controls, we identified 108 genes, from schizophrenia risk genes, that correlated significantly with GMV, which are highly co-expressed in the brain during development. Among these 108 candidates, 19 distinct genes were found associated with 16 brain regions referred to as hot clusters (HCs), primarily in the frontal cortex, sensory-motor regions and temporal and parietal regions. The patients were subtyped into three groups with distinguishable PANSS scores by the GMV of the identified HCs. Furthermore, we found that HCs with common GMV among patient groups are related to genes that mostly mapped to pathways relevant to neural signaling, which are associated with the risk for schizophrenia. Our results provide an integrated view of how genetic variants may affect brain structures that lead to distinct disease phenotypes. The method of multi-scale analysis that was described in this research, may help to advance the understanding of the etiology of schizophrenia., (© The Author(s) (2019). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.)