Schizophrenia is a severe and highly heritable psychiatric disorder affecting approximately 1% of the population. Genome-wide association studies have identified 108 independent genetic loci with genome-wide significance but their functional importance has yet to be elucidated. Here, we develop a novel strategy based on network analysis of protein-protein interactions (PPI) to infer biological function associated with variants most strongly linked to illness risk. We show that the schizophrenia loci are strongly linked to synaptic transmission (P FWE < .001) and ion transmembrane transport (P FWE = .03), but not to ontological categories previously found to be shared across psychiatric illnesses. We demonstrate that brain expression of risk-linked genes within the identified processes is strongly modulated during birth and identify a set of synaptic genes consistently changed across multiple brain regions of adult schizophrenia patients. These results suggest synaptic function as a developmentally determined schizophrenia process supported by the illness's most associated genetic variants and their PPI networks. The implicated genes may be valuable targets for mechanistic experiments and future drug development approaches.
Lamina-specific reductions in dendritic spine density in the prefrontal cortex of subjects with schizophrenia
Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia
Molecular evidence for increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia
Interrogating type 2 diabetes genome-wide association data using a biological pathway-based approach
Analysis of gene expression in two large schizophrenia cohorts identifies multiple changes associated with nerve terminal function
Functional analysis of multiple genomic signatures demonstrates that classification algorithms choose phenotype-related genes
Common inherited variation in mitochondrial genes is not enriched for associations with type 2 diabetes or related glycemic traits
Insights into the neurodevelopmental origin of schizophrenia from postmortem studies of prefrontal cortical circuitry
Transcription and pathway analysis of the superior temporal cortex and anterior prefrontal cortex in schizophrenia
Hidden prenatal malnutrition in the rat: role of β₁-adrenoceptors on synaptic plasticity in the frontal cortex
De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia
Functional consequences of mutations in postsynaptic scaffolding proteins and relevance to psychiatric disorders
Increased prevalence of diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-aspartate glutamate receptor encephalitis
Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.
Protein-protein interaction and pathway analyses of top schizophrenia genes reveal schizophrenia susceptibility genes converge on common molecular networks and enrichment of nucleosome (chromatin) assembly genes in schizophrenia susceptibility loci
Lower gene expression for KCNS3 potassium channel subunit in parvalbumin-containing neurons in the prefrontal cortex in schizophrenia
Differential gene regulation in the anterior cingulate cortex and superior temporal cortex in schizophrenia: A molecular network approach.
Antipsychotic drugs are a class of medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia and bipolar disorder. Discover the latest research on antipsychotic drugs here