Project description:Genome-wide association studies (GWAS) have accelerated the discovery of numerous genetic variants associated with schizophrenia. However, most risk variants show a small effect size (odds ratio (OR)<1.2), suggesting that more functional risk variants remain to be identified. Here, we employed region-based multi-marker analysis of genomic annotation (MAGMA) to identify additional risk loci containing variants with large OR value from Psychiatry Genomics Consortium (PGC2) schizophrenia GWAS data and then employed summary-data-based mendelian randomization (SMR) to prioritize schizophrenia susceptibility genes. The top-ranked susceptibility gene ATP5MD, encoding an ATP synthase membrane subunit, is observed to be downregulated in schizophrenia by the risk allele of CNNM2-rs1926032 in the schizophrenia-associated 10q24.32 locus.
Project description:Large-scale genomic screenings greatly advanced our understanding of the genetic basis of schizophrenia. However, how this translates into neurobiological functioning is not clear. Therefore, we aimed to characterize the function of robust susceptibility gene zinc finger protein 804A (ZNF804A), using a model system of relevant cell type and neurodevelopmental timepoint. Based on previous findings, we hypothesized a role for ZNF804A in local protein translation. CRISPR/Cas9-mediated mutation of the risk gene led to increased synapse formation in human induced pluripotent stem cell (hiPSC)-derived developing glutamatergic forebrain neurons as assessed by high-content confocal imaging. Further, mass spectrometry analysis showed an increased recruitment of ribosomes to mutation neurites. Surface sensing of translation (SUnSET) screening complemented this by demonstrating an increased efficiency of local protein synthesis. Overall, these results introduce a novel cellular function for ZNF804A in a model system relevant to schizophrenia, uncovering some aspects of its neurobiology. Ultimately, findings of this study may aid to identify common mechanisms of susceptibility genes.
Project description:A large portion of common variant loci associated with genetic risk for schizophrenia reside within non-coding sequence of unknown function. Here, we demonstrate promoter and enhancer enrichment in schizophrenia variants associated with expression quantitative trait loci (eQTL). The enrichment is greater when functional annotations derived from human brain are used relative to peripheral tissues. Regulatory trait concordance analysis ranked genes within schizophrenia genome-wide significant loci, based on co-localization of a risk SNP, eQTL and regulatory element sequence. These include physical interactions of non-contiguous gene-proximal and distal elements bypassing the linear genome, which was verified in prefrontal cortex and human induced pluripotent stem cell derived neurons for the L-type calcium channel (CACNA1C) risk locus. Our findings point to a functional link between schizophrenia-associated non-coding SNPs and 3-dimensional genome architecture associated with chromosomal loopings and transcriptional regulation in the brain. Examination of H3K4me3 histone modifications in 3 samples.
Project description:Background Chromosome 16p11.2 is one of the most significant loci in the genome-wide association study (GWAS) of schizophrenia. Despite several integrative analyses and functional genomics studies have been carried out to identify possible risk genes, their impacts in the pathogenesis of schizophrenia remain to be fully characterized. Methods We performed expression quantitative trait loci (eQTL) and summary-data-based Mendelian randomization (SMR) analyses to identify schizophrenia risk genes in the 16p11.2 GWAS locus. We constructed the murine model with dysregulated expression of risk gene in the medial prefrontal cortex (mPFC) using stereotaxic injection of Adeno-associated Virus (AAV), followed by behavioral assessments, dendritic spine analyses and RNA sequencing. Findings We identified significant associations between elevated INO80E mRNA expression in frontal cortex and risk of schizophrenia. The mice overexpressing Ino80e in mPFC (Ino80e-OE) exhibited schizophrenia-like behaviors, including increased anxiety behavior, anhedonia, and impaired prepulse inhibition (PPI) when compared with control group. The neuronal sparse labeling assay showed that the density of mushroom spines in the pyramidal neurons of mPFC was significantly decreased in Ino80e-OE mice compared with control mice, accompanied by a notable increase in the density of stubby spines. Transcriptomic analysis in the mPFC revealed significant alterations in the mRNA levels of schizophrenia-related genes and processes related to synapses upon overexpressing Ino80e . Interpretation Our results suggest that upregulation of the Ino80e gene in mPFC may induce schizophrenia-like behaviors in mice, further supporting the hypothesis that INO80E is an authentic risk gene.
Project description:A large portion of common variant loci associated with genetic risk for schizophrenia reside within non-coding sequence of unknown function. Here, we demonstrate promoter and enhancer enrichment in schizophrenia variants associated with expression quantitative trait loci (eQTL). The enrichment is greater when functional annotations derived from human brain are used relative to peripheral tissues. Regulatory trait concordance analysis ranked genes within schizophrenia genome-wide significant loci, based on co-localization of a risk SNP, eQTL and regulatory element sequence. These include physical interactions of non-contiguous gene-proximal and distal elements bypassing the linear genome, which was verified in prefrontal cortex and human induced pluripotent stem cell derived neurons for the L-type calcium channel (CACNA1C) risk locus. Our findings point to a functional link between schizophrenia-associated non-coding SNPs and 3-dimensional genome architecture associated with chromosomal loopings and transcriptional regulation in the brain.
Project description:Schizophrenia is a highly heritable psychiatric disorder, yet the molecular mechanisms by which genetic risk contributes to disease pathophysiology remain largely unknown. In this study, we investigate the functional consequences of XPO7 loss of function (LoF) in human induced pluripotent stem cell (iPSC)-derived neurons, focusing on its role as a schizophrenia risk gene identified through recent large-scale exome sequencing analyses. By integrating high-precision electrophysiological measurements with transcriptomic, proteomic, and imaging approaches, we demonstrate that XPO7 LoF alters Na+ channel properties and availability, disrupts neuronal excitability, and impairs the synchrony and regularity of network activity. These functional deficits are accompanied by widespread molecular dysregulation affecting nucleocytoplasmic transport, ion channel function, and synaptic composition. Among the dysregulated proteins is Nav1.2, a voltage-gated sodium channel encoded by the schizophrenia-associated gene SCN2A, which exhibits aberrant subcellular distribution in XPO7 LoF neurons, characterized by increased somatic accumulation and reduced synaptic localization. Together, these findings position XPO7 as a critical regulator of neuronal excitability and connectivity, linking channelopathy to cellular phenotypes relevant to schizophrenia pathophysiology.
Project description:Schizophrenia is a complex psychiatric disorder with significant genetic and clinical heterogeneity. Although numerous rare copy number variations (CNVs) with high risk for schizophrenia have been identified, they show no obvious overlap in gene content or function. We hypothesized that the downstream effects of schizophrenia-associated CNVs converge on shared molecular pathways. To test this, we profiled the prefrontal cortex of five schizophrenia-associated CNV mouse models—15q13.3del, 3q29del, 1q21.1del, 22q11.2del, and 16p11.2dup—using single-cell RNA sequencing across two developmental stages: adolescence and adulthood. From 292,943 high-quality single-cell transcriptomes, we identified distinct age- and cell type-specific patterns of differential gene expression and biological pathway perturbations in each model. Rather than converging on a shared molecular mechanism, each CNV affected unique cellular pathways in a developmentally dynamic manner. Notably, genes dysregulated in deep-layer corticothalamic projection neurons from 15q13.3del and 16p11.2dup models, and intratelencephalic neurons from adult 22q11.2del mice, showed enrichment for schizophrenia-SNP heritability. These results support a model in which rare CNVs contribute to schizophrenia genetic risk through developmentally dynamic, distinct pathways rather than through a shared molecular mechanism.
Project description:Genetic association studies provide evidence for a substantial polygenic component to schizophrenia, although the neurobiological mechanisms underlying the disorder remain largely undefined. Building on recent studies supporting a role for developmentally regulated epigenetic variation in the molecular etiology of schizophrenia, this study aimed to identify epigenetic variation associated with both a diagnosis of schizophrenia and elevated polygenic risk burden for the disease across multiple brain regions. Genome-wide DNA methylation was quantified in 262 post-mortem brain samples, representing tissue from four brain regions (prefrontal cortex, striatum, hippocampus and cerebellum) from 41 schizophrenia patients and 47 controls. We identified multiple disease-associated and polygenic risk score-associated differentially methylated positions and regions, many residing in the vicinity of genes previously implicated in schizophrenia including NCAM1, SYNPO, GBP4, PRDM9, GADD45B and DISC1. Our study represents the first analysis of epigenetic variation associated with schizophrenia across multiple brain regions and highlights the utility of polygenic risk scores for identifying molecular pathways associated with etiological variation in complex disease.