Schizophrenia Genes Research Articles

Investigation of OLIG2 as a candidate gene for schizophrenia and autism spectrum disorder.

ABSTRACTA number of genomic mutations that are thought to be strongly involved in the development of schizophrenia (SCZ) and autism spectrum disorder (ASD) have been identified. Abnormalities involving oligodendrocytes have been reported in SCZ, and as a related gene, oligodendrocyte lineage transcription factor 2 (OLIG2) has been reported to be strongly associated with SCZ. In this study, based on the common disease–rare variant hypothesis, target sequencing of candidate genes was performed to identify rare mutations with a high effect size and the possibility that the identified mutations may increase the risks of SCZ and ASD in the Japanese population. In this study, the exon region of OLIG2 was targeted; 370 patients with SCZ and 192 with ASD were subjected to next-generation sequencing. As a result, one rare missense mutation (A33T) was detected. We used the Sanger method to validate this missense mutation with a low frequency (<1%), and then carried out a genetic association analysis involving 3299 unrelated individuals (1447 with SCZ, 380 with ASD, and 1472 healthy controls) to clarify whether A33T was associated with SCZ or ASD. A33T was not found in either case group, and in only one control. We did not find evidence that p.A33T is involved in the onset of ASD or SCZ; however, associations with this variant need to be evaluated in larger samples to confirm our results.

Gene co-expression architecture in peripheral blood in a cohort of remitted first-episode schizophrenia patients

A better understanding of schizophrenia subtypes is necessary to stratify the patients according to clinical attributes. To explore the genomic architecture of schizophrenia symptomatology, we analyzed blood co-expression modules and their association with clinical data from patients in remission after a first episode of schizophrenia. In total, 91 participants of the 2EPS project were included. Gene expression was assessed using the Clariom S Human Array. Weighted-gene co-expression network analysis (WGCNA) was applied to identify modules of co-expressed genes and to test its correlation with global functioning, clinical symptomatology, and premorbid adjustment. Among the 25 modules identified, six modules were significantly correlated with clinical data. These modules could be clustered in two groups according to their correlation with clinical data. Hub genes in each group showing overlap with risk genes for schizophrenia were enriched in biological processes related to metabolic processes, regulation of gene expression, cellular localization and protein transport, immune processes, and neurotrophin pathways. Our results indicate that modules with significant associations with clinical data showed overlap with gene sets previously identified in differential gene-expression analysis in brain, indicating that peripheral tissues could reveal pathogenic mechanisms. Hub genes involved in these modules revealed multiple signaling pathways previously related to schizophrenia, which may represent the complex interplay in the pathological mechanisms behind the disease. These genes could represent potential targets for the development of peripheral biomarkers underlying illness traits in clinical remission stages after a first episode of schizophrenia.

Emerging Roles of FTO in Neuropsychiatric Disorders.

FTO (fat mass and obesity associated) is a recently discovered gene related to obesity and expressed in various tissues of the human body, especially with high expression in the brain. Earlier studies have found that FTO is involved in several biological processes, including brain development and function. In particular, recent studies have found that FTO is a demethylase of N6-methyladenosine (m6A) and it can affect neurological function through the m6A modification of mRNA. At present, a number of studies have shown that FTO is associated with many neuropsychiatric disorders. This paper reviews the discovery, structure, function, and tissue expression of FTO followed by discussing the relationship between FTO and neuropsychiatric diseases. In addition, the potential roles of FTO gene in drug addiction, major depression (MDD), and schizophrenia (SCZ) through regulating m6A modification of dopamine related genes were also highlighted.

Association between MAP3K4 gene polymorphisms and the risk of schizophrenia susceptibility in a Northeast Chinese Han population.

Schizophrenia stands out as one of the most devastating psychiatric disorders. Previous findings have shown that schizophrenia is a polygenic genetic disorder. Thus, abnormal neurodevelopment and neurogenesis may be associated with the etiology of schizophrenia, so genes which affect these processes may be potential candidate genes of schizophrenia. Mitogen-activated protein kinase kinase kinase 4 (MAP3K4) gene is a member of the mitogen-activated protein kinase family. Taking into account previous findings, MAP3K4 plays a crucial role in the fundamental pathology of various nervous system diseases. In the present study, we aim to explore the association of MAP3K4 and schizophrenia in an independent case-control sample including 627 schizophrenic patients and 1175 healthy controls from a Northeast Chinese Han population. Both the allelic and genotypic association analyses showed that 6 SNPs in MAP3K4 were significantly associated with schizophrenia (rs590988, rs625977, rs9295134, rs12110787, rs1001808 and rs9355870). After rigorous Bonferroni correction, 4 SNPs (rs9295134, rs12110787, rs1001808 and rs9355870) were still significantly associated with the disease. The haplotype composed of these four SNPs also showed significantly global and individual association with schizophrenia. These results suggest that MAP3K4 is a susceptibility gene for schizophrenia in the Northeast Chinese Han population.

A conditional gene-based association framework integrating isoform-level eQTL data reveals new susceptibility genes for schizophrenia.

Linkage disequilibrium and disease-associated variants in the non-coding regions make it difficult to distinguish the truly associated genes from the redundantly associated genes for complex diseases. In this study, we proposed a new conditional gene-based framework called eDESE that leveraged an improved effective chi-squared statistic to control the type I error rates and remove the redundant associations. eDESE initially performed the association analysis by mapping variants to genes according to their physical distance. We further demonstrated that the isoform-level eQTLs could be more powerful than the gene-level eQTLs in the association analysis using a simulation study. Then the eQTL-guided strategies, that is, mapping variants to genes according to their gene/isoform-level variant-gene cis-eQTLs associations, were also integrated with eDESE. We then applied eDESE to predict the potential susceptibility genes of schizophrenia and found that the potential susceptibility genes were enriched with many neuronal or synaptic signaling-related terms in the Gene Ontology knowledgebase and antipsychotics-gene interaction terms in the drug-gene interaction database (DGIdb). More importantly, seven potential susceptibility genes identified by eDESE were the target genes of multiple antipsychotics in DrugBank. Comparing the potential susceptibility genes identified by eDESE and other benchmark approaches (i.e., MAGMA and S-PrediXcan) implied that strategy based on the isoform-level eQTLs could be an important supplement for the other two strategies (physical distance and gene-level eQTLs). We have implemented eDESE in our integrative platform KGGSEE (http://pmglab.top/kggsee/#/) and hope that eDESE can facilitate the prediction of candidate susceptibility genes and isoforms for complex diseases in a multi-tissue context.

Dysfunction of cAMP–Protein Kinase A–Calcium Signaling Axis in Striatal Medium Spiny Neurons: A Role in Schizophrenia and Huntington’s Disease Neuropathology

BackgroundStriatal medium spiny neurons (MSNs) are preferentially lost in Huntington’s disease. Genomic studies also implicate a direct role for MSNs in schizophrenia, a psychiatric disorder known to involve cortical neuron dysfunction. It remains unknown whether the two diseases share similar MSN pathogenesis or if neuronal deficits can be attributed to cell type–dependent biological pathways. Transcription factor BCL11B, which is expressed by all MSNs and deep layer cortical neurons, was recently proposed to drive selective neurodegeneration in Huntington’s disease and identified as a candidate risk gene in schizophrenia. MethodsUsing human stem cell–derived neurons lacking BCL11B as a model, we investigated cellular pathology in MSNs and cortical neurons in the context of these disorders. Integrative analyses between differentially expressed transcripts and published genome-wide association study datasets identified cell type–specific disease-related phenotypes. ResultsWe uncover a role for BCL11B in calcium homeostasis in both neuronal types, while deficits in mitochondrial function and PKA (protein kinase A)–dependent calcium transients are detected only in MSNs. Moreover, BCL11B-deficient MSNs display abnormal responses to glutamate and fail to integrate dopaminergic and glutamatergic stimulation, a key feature of striatal neurons in vivo. Gene enrichment analysis reveals overrepresentation of disorder risk genes among BCL11B-regulated pathways, primarily relating to cAMP-PKA-calcium signaling axis and synaptic signaling. ConclusionsOur study indicates that Huntington’s disease and schizophrenia are likely to share neuronal pathophysiology where dysregulation of intracellular calcium homeostasis is found in both striatal and cortical neurons. In contrast, reduction in PKA signaling and abnormal dopamine/glutamate receptor signaling is largely specific to MSNs.

A novel heterozygous missense variant of the ARID4A gene identified in Han Chinese families with schizophrenia-diagnosed siblings that interferes with DNA-binding activity.

ARID4A plays an important role in regulating gene expression and cell proliferation. ARID4A belongs to the AT-rich interaction domain (ARID)-containing family, and a PWWP domain immediately precedes its ARID region. The molecular mechanism and structural basis of ARID4A are largely unknown. Whole-exome sequencing (WES) revealed that a novel heterozygous missense variant, ARID4A c.1231 C > G (p.His411Asp), was associated with schizophrenia (SCZ) in this study. We determined the crystal structure of the PWWP-ARID tandem at 2.05 Å, revealing an unexpected mode in which ARID4A assembles with its PWWP and ARID from a structural and functional supramodule. Our results further showed that compared with the wild type, the p.His411Asp ARID mutant protein adopts a less compact conformation and exhibits a weaker dsDNA-binding ability. The p.His411Asp mutation decreased the number of cells that were arrested in the G0-G1 phase and caused more cells to progress to the G2-M phase. In addition, the missense mutation promoted the proliferation of HEK293T cells. In conclusion, our data provide evidence that ARID4A p.His411Asp could cause a conformational change in the ARID4A ARID domain, influence the DNA binding function, and subsequently disturb the cell cycle arrest in the G1 phase. ARID4A is likely a susceptibility gene for SCZ; thus, these findings provide new insight into the role of ARID4A in psychiatric disorders.

Identification of rare mutations of the vasoactive intestinal peptide receptor 2 gene in schizophrenia.

Studies showed that rare copy number variations (CNVs) encompassing the vasoactive intestinal peptide receptor 2 gene (VIPR2) were associated with schizophrenia, indicating VIPR2 is a risk gene for schizophrenia. We hypothesized that besides CNV, rare pathogenic single-nucleotide variant (SNV) or small insertion/deletion (Indel) of VIPR2 might be present in some patients and contribute to the pathogenesis of schizophrenia. We performed genome-wide CNV analysis to screen CNV at the VIPR2 locus and targeted sequencing of all the exons of VIPR2 to search for SNV and indel in a sample of patients with chronic schizophrenia from Taiwan. We detected a 230-kb microduplication encompassing the VIPR2 in 1 out of 200 patients. Furthermore, we identified six ultrarare SNVs, including one splicing SNV and five missense SNVs, in 516 patients. In-silico analyses showed these SNVs had a damaging effect on the function of VIPR2. Our findings support the idea that besides CNV, rare pathogenic SNVs of VIPR2 might contribute to the pathogenesis of schizophrenia in some patients.

Antipsychotic drugs increase Neuregulin1\u03b21 serum levels in first-episode drug-na\xefve patients and chronic schizophrenia with suggestions for improving the treatment of psychotic symptoms

BackgroundNeuregulin1 (NRG1) plays a role in neuronal migration, regulation of synaptic plasticity, and neural survival, and has been considered to be among the candidate genes for schizophrenia. This study focused on the variations in serum NRG1β1 levels following antipsychotic treatment and the relationship between NRG1β1 levels and improvements in psychotic symptoms among first-episode drug-naïve (FEDN) patients and patients with chronic schizophrenia.MethodsA total of 100 patients with schizophrenia were recruited and compared with 79 matched healthy controls. All patients had been drug-naïve for at least four weeks. Serum NRG1β1 levels and positive and negative syndrome scale (PANSS) scores were measured at baseline and after four weeks. Serum NRG1β1 levels were measured using sandwich enzyme-linked immunosorbent assays (ELISAs).ResultsBaseline NRG1β1 levels were significantly lower in patients with schizophrenia than in healthy controls. NRG1β1 levels increased significantly following antipsychotic treatment. NRG1β1 levels gradually increased with declining PANSS scores and its three subscales during antipsychotic therapy. The levels of NRG1β1 increased significantly in responders after four weeks of treatment, although nonresponders showed no such effect. Correlation analyses showed that the levels of NRG1β1 were negatively correlated with the duration of illness and positively correlated with improvement in symptoms.ConclusionThe levels of serum NRG1β1 and the therapeutic effects gradually increased following treatment, indicating that NRG1β1 may be an indicator of therapy, and that it may also be associated with the pathophysiological mechanism causing schizophrenia, although this possible pathway requires further investigation.

Expansion of Schizophrenia Gene Network Knowledge Using Machine Learning Selected Signals From Dorsolateral Prefrontal Cortex and Amygdala RNA-seq Data.

It is widely accepted, given the complex nature of schizophrenia (SCZ) gene networks, that a few or a small number of genes are unlikely to represent the underlying functional pathways responsible for SCZ pathogenesis. Several studies from large cohorts have been performed to search for key SCZ network genes using different analytical approaches, such as differential expression tests, genome-wide association study (GWAS), copy number variations, and differential methylations, or from the analysis of mutations residing in the coding regions of the genome. However, only a small portion (<10%) of candidate genes identified in these studies were considered SCZ disease-associated genes in SCZ pathways. RNA sequencing (RNA-seq) has been a powerful method to detect functional signals. In this study, we used RNA-seq data from the dorsolateral prefrontal cortex (DLPFC) from 254 individuals and RNA-seq data from the amygdala region from 46 individuals. Analysis was performed using machine learning methods, including random forest and factor analysis, to prioritize the numbers of genes from previous SCZ studies. For genes most differentially expressed between SCZ and healthy controls, 18 were added to known SCZ-associated pathways. These include three genes (GNB2, ITPR1, and PLCB2) for the glutamatergic synapse pathway, six genes (P2RX6, EDNRB, GHR, GRID2, TSPO, and S1PR1) for neuroactive ligand–receptor interaction, eight genes (CAMK2G, MAP2K1, RAF1, PDE3A, RRAS2, VAV1, ATP1B2, and GLI3) for the cAMP signaling pathway, and four genes (GNB2, CAMK2G, ITPR1, and PLCB2) for the dopaminergic synapse pathway. Besides the previously established pathways, 103 additional gene interactions were expanded to SCZ-associated networks, which were shared among both the DLPFC and amygdala regions. The novel knowledge of molecular targets gained from this study brings opportunities for a more complete picture of the SCZ pathogenesis. A noticeable fact is that hub genes, in the expanded networks, are not necessary differentially expressed or containing hotspots from GWAS studies, indicating that individual methods, such as differential expression tests, are not enough to identify the underlying SCZ pathways and that more integrative analysis is required to unfold the pathobiology of SCZ.

Novel missense SETD1A variants in Japanese patients with schizophrenia: Resequencing and association analysis

SETD1A has been identified as a substantial risk gene for schizophrenia. To further investigate the role of SETD1A in the genetic etiology of schizophrenia in the Japanese population, we performed resequencing and association analyses. First, we resequenced the SETD1A coding regions of 974 patients with schizophrenia. Then, we genotyped variants, prioritized via resequencing, in 2,027 patients with schizophrenia and 2,664 controls. Next, we examined the association between SETD1A and schizophrenia in 3,001 patients with schizophrenia and 2,664 controls. Finally, we performed a retrospective chart review of patients with prioritized SETD1A variants. We identified two novel missense variants (p.Ser575Pro and p.Glu857Gln) via resequencing. We did not detect these variants in 4,691 individuals via genotyping. These variants were not significantly associated with schizophrenia in the association analysis. Additionally, we found that a schizophrenia patient with the p.Glu857Gln variant had developmental delays. In conclusion, novel SETD1A missense variants were exclusively identified in Japanese patients with schizophrenia. However, our study does not provide evidence for the contribution of these variants to the genetic etiology of schizophrenia in the Japanese population.

Abnormal RasGRP1 Expression in the Post-Mortem Brain and Blood Serum of Schizophrenia Patients.

Schizophrenia (SCZ) is a polygenic severe mental illness. Genome-wide association studies (GWAS) have detected genomic variants associated with this psychiatric disorder and pathway analyses have indicated immune system and dopamine signaling as core components of risk in dorsolateral-prefrontal cortex (DLPFC) and hippocampus, but the mechanistic links remain unknown. The RasGRP1 gene, encoding for a guanine nucleotide exchange factor, is implicated in dopamine signaling and immune response. RasGRP1 has been identified as a candidate risk gene for SCZ and autoimmune disease, therefore representing a possible point of convergence between mechanisms involving the nervous and the immune system. Here, we investigated RasGRP1 mRNA and protein expression in post-mortem DLPFC and hippocampus of SCZ patients and healthy controls, along with RasGRP1 protein content in the serum of an independent cohort of SCZ patients and control subjects. Differences in RasGRP1 expression between SCZ patients and controls were detected both in DLPFC and peripheral blood of samples analyzed. Our results indicate RasGRP1 may mediate risk for SCZ by involving DLPFC and peripheral blood, thus encouraging further studies to explore its possible role as a biomarker of the disease and/or a target for new medication.

Immune Response Is Key to Genetic Mechanisms of SARS-CoV-2 Infection With Psychiatric Disorders Based on Differential Gene Expression Pattern Analysis.

Existing evidence demonstrates that coronavirus disease 2019 (COVID-19) leads to psychiatric illness, despite its main clinical manifestations affecting the respiratory system. People with mental disorders are more susceptible to COVID-19 than individuals without coexisting mental health disorders, with significantly higher rates of severe illness and mortality in this population. The incidence of new psychiatric diagnoses after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is also remarkably high. SARS-CoV-2 has been reported to use angiotensin-converting enzyme-2 (ACE2) as a receptor for infecting susceptible cells and is expressed in various tissues, including brain tissue. Thus, there is an urgent need to investigate the mechanism linking psychiatric disorders to COVID-19. Using a data set of peripheral blood cells from patients with COVID-19, we compared this to data sets of whole blood collected from patients with psychiatric disorders and used bioinformatics and systems biology approaches to identify genetic links. We found a large number of overlapping immune-related genes between patients infected with SARS-CoV-2 and differentially expressed genes of bipolar disorder (BD), schizophrenia (SZ), and late-onset major depressive disorder (LOD). Many pathways closely related to inflammatory responses, such as MAPK, PPAR, and TGF-β signaling pathways, were observed by enrichment analysis of common differentially expressed genes (DEGs). We also performed a comprehensive analysis of protein–protein interaction network and gene regulation networks. Chemical–protein interaction networks and drug prediction were used to screen potential pharmacologic therapies. We hope that by elucidating the relationship between the pathogenetic processes and genetic mechanisms of infection with SARS-CoV-2 with psychiatric disorders, it will lead to innovative strategies for future research and treatment of psychiatric disorders linked to COVID-19.

Deregulatory miRNA-BDNF Network Inferred from Dynamic Expression Changes in Schizophrenia.

(1) Background: Brain-derived neurotrophic factor (BDNF) is one of the promising risk genes for schizophrenia (SZ), a disease with prominent dysregulation of miRNA networks. Here, we present a study of miRNA-BDNF co-expression changes in peripheral blood of SZ patients. (2) Methods: The expression levels of the BDNF mRNA and three validated binding miRNAs—miR-124-3p, miR-132-3p, and miR-206—were quantified in the blood of 48 healthy controls and 32 SZ patients before and after 12 weeks of treatment. The co-expression patterns were evaluated in the three groups. (3) Results: The expression levels of BDNF were significantly downregulated in SZ patients compared to the controls. After the treatment, the expression levels of BDNF were upregulated, while the expression levels of the three miRNAs were downregulated. Co-expression analyses showed positive correlations of this network in the SZ patients, while weak negative correlations were observed in the healthy controls. After the 12-week treatment, the overall correlation between BDNF and the three miRNAs reached the levels comparable to the healthy controls. (4) Conclusions: Our findings suggest the involvement of the miRNA-BDNF network in the onset and treatment of SZ.

Schizophrenia predisposition gene Unc-51-like kinase 4 for the improvement of cerebral ischemia/reperfusion injury.

Cerebral ischemia/reperfusion injury (CIRI) has complex pathogenesis, and inhibiting apoptosis and supporting neural progenitor proliferation are extremely beneficial strategies for treating CIRI. Unc-51-like kinase 4 (ULK4), a susceptibility gene for schizophrenia, promotes neural progenitors proliferation. The phosphatidylinositol 3-kinase (PI3K) pathway plays a critical role in CIRI via inhibition of apoptosis. Therefore, the relationship among ULK4, the PI3K pathway, and apoptosis in the context of CIRI has attracted our great interest. Primary cortical neurons were subjected to oxygen-glucose deprivation/reperfusion (OGD/R), and rats were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). Transfection of the ULK4-overexpression lentivirus was performed alone or in combination with PI3K inhibitor treatment. Here, we revealed that ULK4 was poorly expressed in the cortex in MCAO/R rats and OGD/R-treated primary cortical neurons, ULK4 overexpression inhibited apoptosis, and reduced neurological deficit scores, cerebral infarct volume, and histopathological damage. Moreover, ULK4 overexpression increased PI3K expression and the p-protein kinase B/AKT and p-glycogen synthase kinase 3 beta (GSK3β)/GSK3β ratios, and inhibited apoptosis, while a PI3K inhibitor reversed the effects of ULK4 overexpression on CIRI. ULK4 protects against CIRI, and the underlying mechanism involves PI3K pathway activation which in turn inhibits apoptosis.

Identification of potential blood biomarkers for early diagnosis of schizophrenia through RNA sequencing analysis

Schizophrenia (SCZ) is a highly heritable, polygenic complex mental disorder with imprecise diagnostic boundaries. Finding sensitive and specific novel biomarkers to improve the biological homogeneity of SCZ diagnosis is still one of the research hotspots. To identify the blood specific diagnostic biomarkers of SCZ, we performed RNA sequencing (RNA-seq) on 30 peripheral blood samples from 15 first-episode drug-naïve SCZ patients and 15 healthy controls (CTL). By performing multiple bioinformatics analysis algorithms based on RNA-seq data and microarray datasets, including differential expression genes (DEGs) analysis, WGCNA and CIBERSORT, we first identified 6 specific key genes (TOMM7, SNRPG, KRT1, AQP10, TMEM14B and CLEC12A) in SCZ. Moreover, we found that the proportions of lymphocyte, monocyte and neutrophils were significantly distinct in SCZ patients with CTL samples. Therefore, combining various features including age, sex and the novel blood biomarkers, we constructed the risk prediction model with three classifiers (RF: Random Forest; SVM: support vector machine; DT: decision tree) through repeated k-fold cross validation ensuring better generalizability. Finest result of Area under Receiver Operating Characteristic (AUROC) score of 0.91 was achieved by RF classifier and with a comparable good performance of AUROC 0.77 in external validation dataset. A lower AUROC of 0.63 was demonstrated when it was further applied to a Bipolar disorder (BPD) cohort. In conclusion, the study identified three peripheral core immunocytes and six key genes associated with the occurrence of SCZ, and further studies are required to test and validate these novel biomarkers for early diagnosis and treatment of SCZ.

Genetic evidence for association of NOTCH4 variant rs2071287 with schizophrenia susceptibility in the North Indian population.

Neurogenic locus notch homolog 4 (NOTCH4) regulates signaling pathways associated with neuronal maturation, a process involved in the development and patterning of the central nervous system. The NOTCH4 gene has also been identified as a possible susceptibility gene for schizophrenia (SCZ). The study aimed to determine the association of NOTCH4 polymorphisms with the risk of SCZ in the North Indian population of the Jammu region. The single nucleotide polymorphism genotyping for NOTCH4 variant rs2071287 was done by Sanger's sequencing method, and the other variant rs3131296 was done by TaqMan assay method for 207 SCZ cases and 304 healthy controls of North Indian origin. This association study suggested that the rs2071287 was found to be significantly associated with SCZ. Moreover, the GG genotype of rs2071287 was observed to be associated with a higher risk for SCZ (P-value = 6.45 × 10 - 5; OR = 1.71; 95% CI, 1.31-2.24). To establish the potential biomarker role of this variant, large-scale association analyses in other populations is required.

Novel open reading frames in human accelerated regions and transposable elements reveal new leads to understand schizophrenia and bipolar disorder

Schizophrenia (SCZ) and bipolar disorder are debilitating neuropsychiatric disorders arising from a combination of environmental and genetic factors. Novel open reading frames (nORFs) are genomic loci that give rise to previously uncharacterized transcripts and protein products. In our previous work, we have shown that nORFs can be biologically regulated and that they may play a role in cancer and rare diseases. More importantly, we have shown that nORFs may emerge in accelerated regions of the genome giving rise to species-specific functions. We hypothesize that nORFs represent a potentially important group of biological factors that may contribute to SCZ and bipolar disorder pathophysiology. Human accelerated regions (HARs) are genomic features showing human-lineage-specific rapid evolution that may be involved in biological regulation and have additionally been found to associate with SCZ genes. Transposable elements (TEs) are another set of genomic features that have been shown to regulate gene expression. As with HARs, their relevance to SCZ has also been suggested. Here, nORFs are investigated in the context of HARs and TEs. This work shows that nORFs whose expression is disrupted in SCZ and bipolar disorder are in close proximity to HARs and TEs and that some of them are significantly associated with SCZ and bipolar disorder genomic hotspots. We also show that nORF encoded proteins can form structures and potentially constitute novel drug targets.

An association study of the HSPA8 gene polymorphisms with schizophrenia in a Polish population

Heat shock cognate 70 (HSC70/HSPA8) is considered to be a promising candidate gene for schizophrenia (SCZ) due to its many essential functions and potential neuroprotective properties in the CNS (e.g., HSC70 is involved in the turnover of the synaptic proteins, synaptic vesicle recycling, and neurotransmitter homeostasis). An alteration in the expression of HSPA8 in SCZ has been reported. This implies that the genetic variants of HSPA8 might contribute to schizophrenia pathogenesis. The present study attempted to determine whether HSPA8 polymorphisms are associated with a susceptibility to schizophrenia or whether they have an impact on the clinical parameters of the disease in a Polish population. A total of 1066 participants (406 patients and 660 controls) were recruited for the study. Five SNPs of the HSPA8 gene (rs2236659, rs1136141, rs10892958, rs1461496, and rs4936770) were genotyped using TaqMan assays. There were no differences in the allele or genotype distribution in any of the SNPs in the entire sample. We also did not find any HSPA8 haplotype-specific associations with SCZ. A gender stratification analysis revealed that an increasing risk of schizophrenia was associated with the rs1461496 genotype in females (OR: 1.68, p < 0.05) in the recessive model. In addition, we found novel associations between HSPA8 SNPs (rs1136141, rs1461496, and rs10892958) and the severity of the psychiatric symptoms as measured by the PANSS. Further studies with larger samples from various ethnic groups are necessary to confirm our findings. Furthermore, studies that explore the functional contribution of the HSPA8 variants to schizophrenia pathogenesis are also needed.

Identification of a Rare Novel KMT2C Mutation That Presents with Schizophrenia in a Multiplex Family.

Schizophrenia is a complex genetic disorder involving many common variants with modest effects and rare mutations with high penetrance. Rare mutations associated with schizophrenia are highly heterogeneous and private for affected individuals and families. Identifying such mutations can help establish the molecular diagnosis, elucidate the pathogenesis, and provide helpful genetic counseling for affected patients and families. We performed a whole-exome sequencing analysis to search for rare pathogenic mutations co-segregating with schizophrenia transmitted in a dominant inheritance in a two-generation multiplex family. We identified a rare missense mutation H1574R (Histidine1574Arginine, rs199796552) of KMT2C (lysine methyltransferase 2C) co-segregating with affected members in this family. The mutation is a novel deleterious mutation of KMT2C, not reported before in the literature. The KMT2C encodes a histone 3 lysine 4 (H3K4)-specific methyltransferase and involves epigenetic regulation of brain gene expression. Mutations of KMT2C have been found in neurodevelopmental disorders, such as Kleefstra syndrome, intellectual disability, and autism spectrum disorders. Our finding suggests that schizophrenia might be one of the clinical phenotype spectra of KMT2C mutations, and KMT2C might be a novel risk gene for schizophrenia. Nevertheless, the co-segregation of this mutation with schizophrenia in this family might also be due to chance; functional assays of this mutation are needed to address this issue.