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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.

Schizophrenia is a debilitating mental disorder and often has a prodromal period, referred to as clinical high risk (CHR) for psychosis, prior to the first episode. The etiology and pathogenesis of schizophrenia remain unclear. Despite the human gut microbiome being associated with schizophrenia, the role of the oral microbiome, which is a vital player in the mouth–body connection, is not well understood. To address this, we performed 16S rRNA gene sequencing to investigate the salivary microbiome in 85 patients with drug-naïve first-episode schizophrenia (FES), 43 individuals at CHR, and 80 healthy controls (HCs). The salivary microbiome of FES patients was characterized by higher α-diversity and lower β-diversity heterogeneity than those of CHR subjects and HCs. Proteobacteria, the predominant phylum, was depleted, while Firmicutes and the Firmicutes/Proteobacteria ratio was enriched, in a stepwise manner from HC to CHR to FES. H2S-producing bacteria exhibited disease-stage-specific enrichment and could be potential diagnostic biomarkers for FES and CHR. Certain salivary microbiota exhibited disease-specific correlation patterns with symptomatic severities, peripheral pro-inflammatory cytokines, thioredoxin, and S100B in FES. Furthermore, the metabolic functions from inferred metagenomes of the salivary microbiome were disrupted in FES, especially amino acid metabolism, carbohydrate metabolism, and xenobiotic degradation. This study has established a link between salivary microbiome alterations and disease initiation and provided the hypothesis of how the oral microbiota could influence schizophrenia.

Risperidone is routinely used in the clinical management of schizophrenia, but the treatment response is highly variable among different patients. The genetic underpinnings of the treatment response are not well understood. We performed a pharmacogenomic study of the treatment response to risperidone in patients with schizophrenia by using a SNP microarray -based genome-wide association study (GWAS) and whole exome sequencing (WES)-based GWAS. DNA samples were collected from 189 patients for the GWAS and from 222 patients for the WES after quality control in multiple centers of China. Antipsychotic response phenotypes of patients who received eight weeks of risperidone treatment were quantified with percentage change on the Positive and Negative Syndrome Scale (PANSS). The GWAS revealed a significant association between several SNPs and treatment response, such as three GRM7 SNPs (rs141134664, rs57521140, and rs73809055). Gene-based analysis in WES revealed 13 genes that were associated with antipsychotic response, such as GPR12 and MAP2K3. We did not identify shared loci or genes between GWAS and WES, but association signals tended to cluster into the GPCR gene family and GPCR signaling pathway, which may play an important role in the treatment response etiology. This study may provide a research paradigm for pharmacogenomic research, and these data provide a promising illustration of our potential to identify genetic variants underlying antipsychotic responses and may ultimately facilitate precision medicine in schizophrenia.

Environmental and genetic factors play important roles in the development of schizophrenia (SCZ), bipolar disorder (BPD) or major depressive disorder (MDD). Some risk loci are identified with shared genetic effects on major psychiatric disorders. To investigate whetherWe focussed on 11 single-nucleotide polymorphisms (SNPs) harbouringWe found that rs3743592 was significantly associated with MDD and rs6498263 with BPD in both allele and genotype distributions. Before correction, rs3743592 showed allelic and genotypic significance with SCZ, rs6498263 showed allelic significance with SCZ. WGCNA identified top 10 modules of co-expressed genes. Gene Ontology (GO) and pathway analysis were used to examine the functions of SNX29, which revealed that SNX29 was involved in the regulation of a number of biological processes, such as TGF-beta, ErbB, and Wnt signalling pathway, etc.Our results supported common risk factors in

Objective Many population studies have shown that maternal prenatal nutrition deficiency may increase the risk of neurodevelopmental disorders in their offspring, but its potential transcriptomic effects on brain development are not clear. We aimed to investigate the transcriptional regulatory interactions between genes in particular pathways responding to the prenatal nutritional deficiency and to explore their effects on neurodevelopment and related disorders. Results We identified three modules in rat hippocampus responding to maternal prenatal nutritional deficiency and found 15 key genes (Hmgn1, Ssbp1, LOC684988, Rpl23, Gga1, Rhobtb2, Dhcr24, Atg9a, Dlgap3, Grm5, Scn2b, Furin, Sh3kbp1, Ubqln1, and Unc13a) related to the rat hippocampus developmental dysregulation, of which Hmgn1, Rhobtb2 and Unc13a related to autism, and Dlgap3, Grm5, Furin and Ubqln1 are related to Alzheimer's disease, and schizophrenia. Transcriptional alterations of the hub genes were confirmed except for Atg9a. Additionally, through modeling miRNA-mRNA-transcription factor interactions for the hub genes, we confirmed a transcription factor, Cebpa, is essential to regulate the expression of Rhobtb2. We did not find singificent singals in the prefrontal cortex responding to maternal prenatal nutritional deficiency. Conclusion These findings demonstrated that these genes with the three modules in rat hippocampus involved in synaptic development, neuronal projection, cognitive function, and learning function are significantly enriched hippocampal CA1 pyramidal neurons and suggest that three genetic regulatory subnetworks and thirteen key regulating genes in rat hippocampus perturbed by a prenatal nutrition deficiency. These genes and related subnetworks may be prenatally involved in the etiologies of major brain disorders, including Alzheimer's disease, autism, and schizophrenia. Methods We compared the transcriptomic differences in the hippocampus and prefrontal cortex between 10 rats with prenatal nutritional deficiency and 10 rats with prenatal normal chow feeding by differential analysis and co-expression network analysis. A network-driven integrative analysis with microRNAs and transcription factors was performed to define significant modules and hub genes responding to prenatal nutritional deficiency. Meanwhile, the module preservation test was conducted between the hippocampus and prefrontal cortex. Expression levels of the hub genes were further validated with a quantitative real-time polymerase chain reaction based on additional 40 pairs of rats.

Summary: TENM4, encoding a member of the teneurin protein family, is a risk gene shared by many types of mental diseases and is implicated in neuronal plasticity and signaling. However, the role and the mechanisms of TENM4 in schizophrenia (SCZ) remain unclear. We identified possible pathogenic mutations in the TENM4 gene through target sequencing of TENM4 in 68 SCZ families. We further demonstrated that aberrant expression of Ten-m leads to lower learning ability, sleep reduction, and increased aggressiveness in animal models. RNA sequencing showed that aberrant expression of Ten-m was related to stimulus perception and metabolic process, and Gene Ontology enrichment terms were neurogenesis and ATPase activity. This study provides strong evidence that TENM4 contributes to SCZ, and its functional mutations might be responsible for the impaired neural circuits and behaviors observed in SCZ.

Background Clozapine is considered to be the most effective antipsychotic medication for schizophrenia. However, it is associated with several adverse effects such as leukopenia, and the underlying mechanism has not yet been fully elucidated. The authors performed a genome-wide association study (GWAS) in a Chinese population to identify genetic markers for clozapine-induced leukopenia (CIL) and clozapine-induced neutropenia (CIN). Methods A total of 1879 patients (225 CIL cases, including 43 CIN cases, and 1,654 controls) of Chinese descent were included. Data from common and rare single nucleotide polymorphisms (SNPs) were tested for association. The authors also performed a trans-ancestry meta-analysis with GWAS results of European individuals from the Clozapine-Induced Agranulocytosis Consortium (CIAC). Results The authors identified several novel loci reaching the threshold of genome-wide significance level (P −8). Three novel loci were associated with CIL while six were associated with CIN, and two T cell related genes (TRAC and TRAT1) were implicated. The authors also observed that one locus with evidence close to genome-wide significance (P = 5.08 × 10−8) was near the HLA-B gene in the major histocompatibility complex region in the trans-ancestry meta-analysis. Conclusions The associations provide novel and valuable understanding of the genetic and immune causes of CIL and CIN, which is useful for improving clinical management of clozapine related treatment for schizophrenia. Causal variants and related underlying molecular mechanisms need to be understood in future developments.

Olanzapine is an effective antipsychotic medication for treatment-resistant schizophrenia (TRS); however, the therapeutic effectiveness of olanzapine has been found to vary in individual patients. It is imperative to unravel its resistance mechanisms and find reliable targets to develop novel precise therapeutic strategies.Unbiased RNA sequencing analysis was performed using homogeneous populations of neural stem cells derived from induced pluripotent stem cells in 3 olanzapine responder (reduction of Positive and Negative Syndrome Scale score ≥25%) and 4 nonresponder (reduction of Positive and Negative Syndrome Scale score25%) inpatients with TRS. We also used a genotyping study from patients with TRS to assess the candidate genes associated with the olanzapine response. CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9-mediated genome editing, neurologic behavioral tests, RNA silencing, and microRNA sequencing were used to investigate the phenotypic mechanisms of an olanzapine resistance gene in patients with TRS.Neuregulin-1 (NRG-1) deficiency-induced mitochondrial dysfunction is associated with olanzapine treatment outcomes in TRS. NRG-1 knockout mice showed schizophrenia-relevant behavioral deficits and yielded olanzapine resistance. Notably, miR143-3p is a critical NRG-1 target related to mitochondrial dysfunction, and miR143-3p levels in neural stem cells associate with severity to olanzapine resistance in TRS. Meanwhile, olanzapine resistance in NRG-1 knockout mice could be rescued by treatment with miR143-3p agomir via intracerebral injection.Our findings provide direct evidence of olanzapine resistance resulting from NRG-1 deficiency-induced mitochondrial dysfunction, and they link olanzapine resistance and NRG-1 deficiency-induced mitochondrial dysfunction to an NRG-1/miR143-3p axis, which constitutes a novel biomarker and target for TRS.

Summary Schizophrenia (SCZ) is a severe neuropsychiatric disorder that affects 1% of the global population. Copy number variations (CNVs) have been shown to play a critical role in its pathophysiology; however, only case-control studies on SCZ susceptibility CNVs have been conducted in Han Chinese. Here, we performed an array comparative genomic hybridization-based genome-wide CNV analysis in 100 Chinese family trios with SCZ. Burden test suggested that the SCZ probands carried more duplications than their healthy parents and unrelated healthy controls. Besides, five CNV loci were firstly reported to be associated with SCZ here, including both unbalanced transmitted CNVs and enriched de novo CNVs. Moreover, two genes (CTDSPL and MGAM) in these CNVs showed significant SCZ relevance in the expression level. Our findings support the crucial role of CNVs in the etiology of SCZ and provide new insights into the underlying mechanism of SCZ pathogenesis., Graphical abstract, Highlights • Copy number changes of 3p22.2, 7p13, 11p15.1, 12p13, and 6p12 are associated with SCZ • The under-transmission of CTDSPL contributes to SCZ susceptibility, Genetics; Genomics; Psychology

Background At present, the schizophrenia diagnoses are based on the clinical symptoms and behaviors neglecting the laboratory test indicators. Results To better investigate the diagnostic potential of miRNAs for schizophrenia, we selected 14 candidate miRNAs and examined their expressions in the serums of 40 schizophrenia patients and 40 healthy controls by qRT-PCR. Ultimately three abnormally expressed microRNAs were identified, i.e., miR-34a-5p, miR-432-5p and miR-449a. Then, binary regression analysis was employed to combine 3 dysregulated miRNAs. ROC analysis revealed that the AUC of the combination of miR-432-5p + miR-449a in serums was 0.841 (95% CI: 0.791~0.887) with 90% sensitivity and 80% specificity. The AUC of the combination of miR-34a-5p + miR-432-5p + miR-449a in serums was 0.843 (95% CI: 0.791~0.887) with 90% sensitivity and 77.5% specificity. The results indicated that the combined model of miR-432-5p + miR-449a and miR-34a-5p + miR-432-5p + miR-449a have better prediction performances. Conclusions The study concludes that the two miRNAs combinations have the potential to be used as biomarkers for schizophrenia diagnoses. The finding may be conducive to overcoming the dilemmas faced by current schizophrenia diagnosis.

Background: Schizophrenia (SCZ) is a complex, heritable, and devastating psychiatric disorder. Mutations in the members of ABC transporters have been associated with psychiatric illnesses. Aims: In this study, we investigated whether 9 SNPs in ABCB1 (rs6946119, rs28401781, rs4148739, and rs3747802), ABCB6 (rs1109866, rs1109867, rs3731885, and rs3755047), and ABCG1 (rs182694) contribute to the risk of SCZ in a Han Chinese population. Methods: We conducted a case-control study in a Han Chinese population, involving 1,034 SCZ patients and 1,034 unrelated healthy controls to genotype 9 SNPs. Results: The analysis demonstrated that rs182694 of ABCG1 was significantly different between SCZ patients and controls as to allele (rs182694: p = 0.0070, χ2 = 7.27) and genotype frequencies (rs182694: p = 0.0013, χ2 = 13.35). Conclusions: Our findings support an association between ABCG1 polymorphism and SCZ in a Han Chinese population.

Objective Violent behaviour is an alarming problem among schizophrenia patients. The effects of historical, clinical, and pathological risk factors for violence have been investigated by multiple studies, but consensus has not been achieved. As psychotic symptoms are more direct and intuitive indicators for violence, identifying robustly associated symptoms is a crucial part of the future prediction and precise management of violent patients in clinics. This study aims to identify the psychotic symptoms correlated with violence among schizophrenia patients in a Chinese population. Methods In this cross-sectional study, the medical records of 7711 schizophrenia patients (4711 in the discovery set and 3000 in the validation set) were collected from 1998 to 2010. Their psychotic symptoms were extracted, and the patients were divided into violent and non-violent groups. Multivariate logistic analysis was applied to identify symptoms associated with violence in the discovery set. Results Eight psychotic symptoms were found to be significantly correlated with violence in schizophrenia. “Destruction of property”, “verbal aggression” and “insomnia” increased the risk of violence, while “flat affect”, “delusion of persecution”, “auditory hallucination”, “vagueness of thought” and “poverty of thought” decreased the risk of violence. The regression model was evaluated by receiver operating characteristic (ROC) analysis for its discriminatory performance, achieving area under curve (AUC) values of 0.887 in the discovery sample set and 0.824 in the validation sample set. Conclusions The correlated symptoms identified by this study can serve as future candidate predictors for violence in schizophrenia, paving the way for precise management of schizophrenia patients in clinics.

Schizophrenia (SCZ) is a severe psychiatric disorder with a strong genetic component. High heritability of SCZ suggests a major role for transmitted genetic variants. Furthermore, SCZ is also associated with a marked reduction in fecundity, leading to the hypothesis that alleles with large effects on risk might often occur de novo. In this study, we conducted whole-genome sequencing for 23 families from two cohorts with unaffected siblings and parents. Two nonsense de novo mutations (DNMs) in GJC1 and HIST1H2AD were identified in SCZ patients. Ten genes (DPYSL2, NBPF1, SDK1, ZNF595, ZNF718, GCNT2, SNX9, AACS, KCNQ1, and MSI2) were found to carry more DNMs in SCZ patients than their unaffected siblings by burden test. Expression analyses indicated that these DNM implicated genes showed significantly higher expression in prefrontal cortex in prenatal stage. The DNM in the GJC1 gene is highly likely a loss function mutation (pLI = 0.94), leading to the dysregulation of ion channel in the glutamatergic excitatory neurons. Analysis of rare variants in independent exome sequencing dataset indicates that GJC1 has significantly more rare variants in SCZ patients than in unaffected controls. Data from genome-wide association studies suggested that common variants in the GJC1 gene may be associated with SCZ and SCZ-related traits. Genes co-expressed with GJC1 are involved in SCZ, SCZ-associated pathways, and drug targets. These evidences suggest that GJC1 may be a risk gene for SCZ and its function may be involved in prenatal and early neurodevelopment, a vulnerable period for developmental disorders such as SCZ.

Testosterone has historically been linked to sexual dysfunction, however, it has recently been shown to affect other physical and mental attributes. We attempted to determine whether changes in serum testosterone could play a role in chronic or degenerative diseases. We used two separate genetic instruments comprising of variants from JMJD1C and SHBG regions and conducted a two-sample Mendelian randomization for type II diabetes (T2D), gout, rheumatoid arthritis (RA), schizophrenia, bipolar disorder, Alzheimer&rsquo, s disease and depression. For the JMJD1C locus, one unit increase in log transformed testosterone was significantly associated with RA (OR = 1.69, p = 0.02), gout (OR = 0.469, p = 0.001) and T2D (OR = 0.769, p = 0.048). Similarly, one unit increase in log transformed testosterone using variants from the SHBG locus was associated with depression (OR = 1.02, p &lt, 0.0001), RA (OR = 1.254, p &lt, 0.0001) and T2D (OR = 0.88, p &lt, 0.0001). Our results show that low levels of serum testosterone levels may cause gout and T2D, while higher than normal levels of testosterone may result in RA and depression. Our findings suggest that fluctuations in testosterone levels may have severe consequences that warrant further investigation.

Aim To determine whether interleukin 18 (IL-18) is elevated in the blood of schizophrenia (SCZ) and first episode psychosis patients, as well as investigate whether this potential relationship is causal. Method We conducted a systematic review and meta-analysis of IL-18 levels in the blood of SCZ patients, comprising of both chronic and first episode psychosis (FEP) cohorts. To investigate causality, we undertook the two-sample Mendelian randomization (MR) study. Results A total of eight studies were included in our meta-analysis, our results did indeed show an association between elevated levels of IL-18 and SCZ compared to healthy controls (Z = 3.50, P = .0005). This association remained significant in subsequent subgroup analyses for chronic (Z = 3.15, P = .002) and achieved borderline significance in FEP (Z = 1.93, P = .05) SCZ. Our MR analysis failed to detect any causal relationship between IL-18 levels and SCZ. Conclusion The results of our study demonstrate that even though IL-18 levels are elevated in SCZ patients, IL-18 levels do not seem to cause of the disorder itself. Our findings suggest that IL-18 may have utility as a biomarker of SCZ and aid in research into the early intervention of the disease.

International audience; Objective: Cannabis consumption during adolescence has been reported as a risk factor for psychotic-like experiences (PLEs) and schizophrenia. However, brain developmental processes associated with cannabis-related PLEs are still poorly described.Method: A total of 706 adolescents from the general population who were recruited by the IMAGEN consortium had structural magnetic resonance imaging scans at both 14 and 19 years of age. We used deformation-based morphometry to map voxelwise brain changes between the two time points, using the pairwise algorithm in SPM12b. We used an a priori region-of-interest approach focusing on the hippocampus/parahippocampus to perform voxelwise linear regressions. Lifetime cannabis consumption was assessed using the European School Survey Project on Alcohol and other Drugs (ESPAD), and PLEs were assessed with the Comprehensive Assessment Psychotic-like experiences (CAPE) tool. We first tested whether hippocampus/parahippocampus development was associated with PLEs. Then we formulated and tested an a priori simple mediation model in which uncus development mediates the association between lifetime cannabis consumption and PLEs.Results: We found that PLEs were associated with reduced expansion within a specific region of the right hippocampus/parahippocampus formation, the uncus (p = .002 at the cluster level, p = .018 at the peak level). The partial simple mediation model revealed a significant total effect from lifetime cannabis consumption to PLEs (b = 0.069, 95% CI = 0.04−0.1, p =2 × 10−16), as well as a small yet significant, indirect effect of right uncus development (0.004; 95% CI = 0.0004−0.01, p = .026).Conclusion: We show here that the uncus development is involved in the cerebral basis of PLEs in a population-based sample of healthy adolescents

Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, potentially missing important biological insights. Here, we report the largest study to date of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide significant associations in 19 genetic loci. Common genetic variants that confer risk for schizophrenia have highly similar effects between East Asian and European ancestries (rg = 0.98 ± 0.03), indicating that the genetic basis of schizophrenia and its biology are broadly shared across populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries identified 208 significant associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping reduced the sets of candidate causal variants in 44 loci. Polygenic risk scores had reduced performance when transferred across ancestries, highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations., Editorial summary: Genome-wide meta-analysis with individuals of East Asian or European ancestry identifies 176 loci associated with schizophrenia. Despite consistent genetic effects across populations, polygenic risk models trained in one population have reduced performance in the other population.

Schizophrenia (SCZ) is a severe psychiatric disorder with a strong genetic component. High heritability of SCZ suggests a major role for transmitted genetic variants. Furthermore, SCZ is also associated with a marked reduction in fecundity, leading to the hypothesis that alleles with large effects on risk might often occur de novo. In this study, we conducted whole-genome sequencing for 23 families from two cohorts with matched unaffected siblings and parents. Two nonsensede novomutations (DNMs) inGJC1andHIST1H2ADwere identified in SCZ patients. Ten genes (DPYSL2, NBPF1, SDK1, ZNF595, ZNF718, GCNT2, SNX9, AACS, KCNQ1andMSI2) were found to carry more DNMs in SCZ patients than their unaffected siblings by burden test. Expression analyses indicated that these DNM implicated genes showed significantly higher expression in prefrontal cortex in prenatal stage. The DNM in theGJC1gene is highly likely a loss function mutation (pLI = 0.94), leading to the dysregulation of ion channel in the glutamatergic excitatory neurons. Analysis of rare variants in independent exome sequencing dataset indicates thatGJC1has significantly more rare variants in SCZ patients than in unaffected controls. Data from genome-wide association studies suggested that common variants in theGJC1gene may be associated with SCZ and SCZ-related traits. Genes co-expressed withGJC1are involved in SCZ, SCZ-associated pathways and drug targets. These evidence suggest thatGJC1may be a risk gene for SCZ and its function may be involved in prenatal and early neurodevelopment, a vulnerable period for developmental disorders such as SCZ.

Schizophrenia (SCZ) is a devastating genetic mental disorder. Identification of the SCZ risk genes in brains is helpful to understand this disease. Thus, we first used the minimum Redundancy-Maximum Relevance (mRMR) approach to integrate the genome-wide sequence analysis results on SCZ and the expression quantitative trait locus (eQTL) data from ten brain tissues to identify the genes related to SCZ. Second, we adopted the variance inflation factor regression algorithm to identify their interacting genes in brains. Third, using multiple analysis methods, we explored and validated their roles. By means of the aforementioned procedures, we have found that (1) the cerebellum may play a crucial role in the pathogenesis of SCZ and (2) ITIH4 may be utilized as a clinical biomarker for the diagnosis of SCZ. These interesting findings may stimulate novel strategy for developing new drugs against SCZ. It has not escaped our notice that the approach reported here is of use for studying many other genome diseases as well. Keywords: schizophrenia, eQTL, mRMR, SNP, GTEx, brain, GO, YWHA, EIF2, ITIH4

Background Schizophrenia (SCZ) is a severe psychiatric disorder that affects approximately 0.75% of the global population. Both genetic and environmental factors contribute to development of SCZ. SCZ tends to run in family while both genetic and environmental factor contribute to its etiology. Much evidence suggested that alterations in DNA methylations occurred in SCZ patients. Methods To investigate potential inheritable pattern of DNA methylation in SCZ family, we performed a genome-wide analysis of DNA methylation of peripheral blood samples from 106 Chinese SCZ family trios. Genome-wide DNA methylations were quantified by Agilent 1 × 244 k Human Methylation Microarray. Findings In this study, we proposed a loci inheritance frequency model that allows characterization of differential methylated regions as SCZ biomarkers. Based on this model, 112 hypermethylated and 125 hypomethylated regions were identified. Additionally, 121 hypermethylated and 139 hypomethylated genes were annotated. The results of functional enrichment analysis indicated that multiple differentially methylated genes (DMGs) involved in Notch/HH/Wnt signaling, MAPK signaling, GPCR signaling, immune response signaling. Notably, a number of hypomethylated genes were significantly enriched in cerebral cortex and functionally enriched in nervous system development. Interpretation Our findings not only validated previously discovered risk genes of SCZ but also identified novel candidate DMGs in SCZ. These results may further the understanding of altered DNA methylations in SCZ. Funding None.

Schizophrenia (SCZ) is a common mental disorder with high heritability, and genetic factors play a major role in the pathogenesis. Recent researches indicated that the CACNA1I involved in calcium channels probably affect the potential pathogenesis of SCZ. In this study, we attempted to investigate whether the CACNA1I gene contributes the risk to SCZ in the Uighur Chinese population, and performed a case-control study involving 985 patient samples and 1218 normal controls to analyze nine SNPs within the CACNA1I gene. Among these sites, six SNPs were significantly associated with SCZ in the allele distribution: rs132575 (adjusted P allele = 0.039, OR = 1.159), rs713860 (adjusted P allele = 0.039, OR = 0.792), rs738168 (adjusted P allele = 0.039, OR = 0.785), rs136805 (adjusted P allele = 0.014, OR = 1.212), rs5757760 (adjusted P allele = 0.042, OR = 0.873) and rs5750871 (adjusted P allele = 0.039, OR = 0.859). In addition, two SNPs turned to be risk factors for SCZ not only in the allele distribution, but also in the genotype distribution: rs132575 (adjusted P genotype = 0.037) and rs136805 (adjusted P genotype = 0.037). Overall, the present study provided evidence that significant association exists between the CACNA1I gene and SCZ in the Uighur Chinese population, subsequent validation of functional analysis and genetic association studies are needed to further extend this study.

Schizophrenia is a highly heritable psychiatric disorder often associated with dopamine-related genetic variations. Thus, we performed a case-control study in 1504 Han Chinese population to evaluate the association of DRD1, DRD2 and DRD3 polymorphisms with schizophrenia. No statistically significant difference in allelic or genotypic frequency was found between schizophrenia and control subjects. Strong positive linkage disequilibrium was detected among the SNPs within DRD1 and DRD2. However, no positive haplotype distribution was found to be associated with schizophrenia. Our results indicated that DRD1, DRD2 and DRD3 may not be the susceptibility genes for schizophrenia in the Chinese Han population.

Schizophrenia is a severe and complex mental disorder with high heritability. There is evidence that mutations in the gene of Nmethyl-d-aspartate-type glutamate receptors (NMDAR) are associated with schizophrenia. GRIN2B encodes a subunit of NMDARs, and has been identified as a candidate gene for many psychiatric disorders, especially schizophrenia. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in GRIN2B were associated with schizophrenia. Four SNPs (rs890, rs1806191, rs219872, rs172677) were genotyped in 752 schizophrenic patients and 846 healthy controls of the Chinese Han population. Our results indicate differences in allele and genotype frequencies of rs890 between case and control. These results were assessed by adapting different genetic models (codominant, dominant, recessive, overdominant, log-additive models). After controlling for confounding factors including sex and age, rs890 remained associated with schizophrenia. In addition, rs890 and rs1806191 were found to form a haplotype associated with schizophrenia. In summary, our results indicate that the GRIN2B SNP rs890 might be associated with schizophrenia in the Chinese Han population.

Schizophrenia (SCZ) is a highly heritable psychiatric disorder that affects approximately 1% of population around the world. However, early relevant studies did not reach clear conclusions of the genetic mechanisms of SCZ, suggesting that additional susceptibility loci that exert significant influence on SCZ are yet to be revealed. So, in order to identify novel susceptibility genes that account for the genetic risk of SCZ, we performed a systematic family-based study using whole exome sequencing (WES) in 65 Han Chinese families. The analysis of 51 SCZ trios with both unaffected parents identified 22 exonic and 1 splice-site de novo mutations (DNMs) on a total of 23 genes, and showed that 12 genes carried rare protein-altering compound heterozygous mutations in more than one trio. In addition, we identified 26 exonic or splice-site single nucleotide polymorphisms (SNPs) on 18 genes with nominal significance (P −4) using a transmission disequilibrium test (TDT) in all the families. Moreover, TDT result confirmed a SCZ susceptibility locus on 3p21.1, encompassing the multigenetic region NEK4-ITIH1-ITIH3-ITIH4. Through several different strategies to predict the potential pathogenic genes in silico, we revealed 4 previous discovered susceptibility genes (TSNARE1, PBRM1, STAB1 and OLIG2) and 4 novel susceptibility loci (PSEN1, TLR5, MGAT5B and SSPO) in Han Chinese SCZ patients. In summary, we identified a list of putative candidate genes for SCZ using a family-based WES approach, thus improving our understanding of the pathology of SCZ and providing critical clues to future functional validation.

Schizophrenia is a kind of neurodevelopmental disease. Epidemiological data associates schizophrenia with prenatal exposure to famine. Relevant prenatal protein deprivation (PPD) rodent models support this result by observing decreasing prepulse inhibition, altered hippocampal morphology and impaired memory in offspring. All these abnormalities are highly consistent with the pathophysiology of schizophrenia. We developed a prenatal famine rat model by restricting daily diet of the pregnant rat to 50% of low protein diet. A metabolomics study of prefrontal cortex was performed to integrate GC-TOFMS and UPLC-QTOFMS. Thirteen controls and thirteen famine offspring were used to differentiate in PLS-DA (partial least squares-discriminate analysis) model. Furthermore, metabolic pathways and diseases were enriched via KEGG and HMDB databases, respectively. A total of 67 important metabolites were screened out according to the multivariate analysis. Schizophrenia was the most statistical significant disease (P = 0.0016) in our famine model. These metabolites were enriched in key metabolic pathways related to energy metabolism and glutamate metabolism. Based on these important metabolites, further discussion speculated famine group was characterized by higher level of oxidized damage compared to control group. We proposed that oxidative stress might be the pathogenesis of prenatal undernutrition which is induced schizophrenia.

Schizophrenia (SCZ) is a complex, heritable, and devastating psychiatric disorder. Mutations in the members of ABC transporters have been associated with psychiatric illnesses.In this study, we investigated whether 9 SNPs in ABCB1 (rs6946119, rs28401781, rs4148739, and rs3747802), ABCB6 (rs1109866, rs1109867, rs3731885, and rs3755047), and ABCG1 (rs182694) contribute to the risk of SCZ in a Han Chinese population.We conducted a case-control study in a Han Chinese population, involving 1,034 SCZ patients and 1,034 unrelated healthy controls to genotype 9 SNPs.The analysis demonstrated that rs182694 of ABCG1 was significantly different between SCZ patients and controls as to allele (rs182694: p = 0.0070, χ2 = 7.27) and genotype frequencies (rs182694: p = 0.0013, χ2 = 13.35).Our findings support an association between ABCG1 polymorphism and SCZ in a Han Chinese population.

Compelling evidence suggested the role of copy number variations (CNVs) in schizophrenia susceptibility. Most of the evidence was from studies in populations with European ancestry. We tried to validate the associated CNV loci in a Han Chinese population and identify novel loci conferring risk of schizophrenia.We performed a genome-wide CNV analysis on 6588 patients with schizophrenia and 11,904 control subjects of Han Chinese ancestry.Our data confirmed increased genome-wide CNV (500 kb and1%) burden in schizophrenia, and the increasing trend was more significant when only1 Mb CNVs were considered. We also replicated several associated loci that were previously identified in European populations, including duplications at 16p11.2, 15q11.2-13.1, 7q11.23, and VIPR2 and deletions at 22q11.2, 1q21.1-q21.2, and NRXN1. In addition, we discovered three additional new potential loci (odds ratio6, p.05): duplications at 1p36.32, 10p12.1, and 13q13.3, involving many neurodevelopmental and synaptic related genes.Our findings provide further support for the role of CNVs in the etiology of schizophrenia.

BackgroundA large schizophrenia genome-wide association study (GWAS) and a subsequent extensive replication study of individuals of European ancestry identified eight new loci with genome-wide significance and suggested that theMIR137-mediated pathway plays a role in the predisposition for schizophrenia.AimsTo validate the above findings in a Han Chinese population.MethodWe analysed the single nucleotide polymorphisms (SNPs) in the newly identified schizophrenia candidate loci and predictedMIR137target genes based on our published Han Chinese populations (BIOX) GWAS data. We then analysed 18 SNPs from the candidate regions in an independent cohort that consisted of 3585 patients with schizophrenia and 5496 controls of Han Chinese ancestry.ResultsWe replicated the associations of five markers (PMIR137target genes. Two loci (ITIH3/4: rs2239547,P=1.17×10–10andCALN1: rs2944829,P=9.97×10–9) exhibited genome-wide significance in the Han Chinese population.ConclusionsTheITIH3/4locus has been reported to be of genome-wide significance in the European population. The successful replication of this finding in a different ethnic group provides stronger evidence for the association between schizophrenia andITIH3/4. We detected the first genome-wide significant association of schizophrenia withCALN1, which is a predicted target ofMIR137, and thus provide new evidence for the associations betweenMIR137targets and schizophrenia.

The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.

Schizophrenia is a severe and complex mental disorder with high heritability. There is an evidence that metabotropic glutamate receptors (GRM) are associated with schizophrenia. GRM7 has been identified as a candidate gene for many psychiatric disorders especially schizophrenia. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in GRM7 were associated with schizophrenia. Four SNPs (rs9814881, rs13353402, rs9870680 and rs1531939) were genotyped in 1034 schizophrenic patients and 1034 healthy controls of Chinese Han origin. The results showed that the two SNPs rs13353402 and rs1531939 demonstrated significant difference between schizophrenic patients and control subjects in allele frequencies (rs13353402: P value=0.0307, rs1531939: P value=0.0328, respectively). Nevertheless, there was no significant discrepancies in genotype distribution. In summary, our results indicate that the GRM7 SNPs rs13353402 and rs1531939 might be associated with schizophrenia in Chinese Han population.

This study was intended to ascertain whether SNPs in dopaminergic and serotoninergic pathway genes SLC6A2, SLC6A3 and DRD2 are associated with schizophrenia in Han Chinese people. We conducted a case-control study by genotyping 7 SNPs of the three genes in 1034 schizophrenia patients and 1034 controls. No significant difference in the allelic or genotypic frequency was detected between cases and controls despite one positive haplotype (rs1362621-rs2242446-rs5564). Stratified analysis of gender and gene-gene interaction analysis showed no positive results. In summary, our study denies the major role of these SNPs within the three genes for schizophrenia in Han Chinese.

Background The link between schizophrenia and diabetes mellitus is well established by observational studies; however, the cause-effect relationship remains unclear. Methods Here, we conducted Mendelian randomization analyses to assess a causal relationship of the genetic variants related to elevated fasting glucose levels, hemoglobin A1c (HbA1c), fasting insulin levels, and type 2 diabetes with the risk of schizophrenia. The analyses were performed using summary statistics obtained for the variants identified from the genome-wide association meta-analyses of fasting glucose levels (up to 133,010 individuals), HbA1c (up to 153,377 individuals), fasting insulin levels (up to 108,557 individuals), type 2 diabetes (up to 659,316 individuals), and schizophrenia (up to 108,341 individuals). The association between each variant and schizophrenia was weighted by its association with each studied condition, and estimates were combined using an inverse-variance weighted meta-analysis. Findings Using information from thirteen variants related to fasting insulin levels, the causal effect of fasting insulin levels increases (per 1-SD) on the risk of schizophrenia was estimated at an odds ratio (OR) of 2·33 (p = 0·001), which is consistent with findings from the observational studies. The fasting glucose associated single nucleotide polymorphisms (SNPs) had no effect on the risk of schizophrenia in Europeans and East Asians (p > 0·05). Nonsignificant effects on the risk of schizophrenia was observed with raised HbA1c and type 2 diabetes, and consistent estimates were obtained across different populations. Interpretation Our results suggest a causal role of elevated fasting insulin levels in schizophrenia pathogenesis.

The distal long arm of chromosome 22 (22q13.3) may harbor genes implicated in schizophrenia. This is evidenced by various genetic mapping studies. BRD1 and its neighboring gene ZBED4, both located within this region, have repeatedly been found to be associated with schizophrenia in the Caucasian population. In this study, we chose seven SNPs (two BRD1 SNPs, five ZBED4 SNPs) to carry out an association study between these two genes and schizophrenia in the Chinese population. However, no significant result was obtained, which was consistent with the Japanese population. Taken together, we could conclude that BRD1 and ZBED4 might be population specific in schizophrenia and may not account for a substantial proportion of genetic risk for schizophrenia in the Asian population.