Affiliate stigma and its association with family burden among family members of people living with schizophrenia in China.

PURPOSE: Understanding affiliate stigma and its impact on family of people living with schizophrenia (PLS) in China is important for culturally informed intervention. This study aims to describe the pattern of affiliate stigma of family members of PLS in China and investigated the association between affiliate stigma and family burden. METHODS: PLS and their family members dwelling in community were randomly recruited from four cities across China and completed measures of affiliate stigma and family burden. Linear regression analyses were used to determine the association between affiliate stigma and family burden. RESULTS: A total of 493 dyads of family member and PLS were include in this study. The mean affiliate stigma in family members was 2.21 (SD = 0.61). The vast majority of family members reported the feeling of inferiority, helpless and sad because of their family members' schizophrenia, but few family members refusing to communicate or contact with the PLS. The mean score of overall family burden was 22.25 (SD = 14.90), with 98 % of participants reported moderate or severe burden. A higher level of affiliate stigma was associated with more family burden (b = 7.837, 95CI: 5.240 to 8.747). Affiliate stigma was significantly associated with family daily activities, entertainment activities, family relationship, physical health and mental health of family members, but not family economic burden. CONCLUSION: A higher level of affiliate stigma was associated with more family burden among family with PLS. Anti-stigma intervention of mental illness should be consider not only PLS but also their family members.

Linguistic and (micro)cultural differences in the global debate about re-naming 'schizophrenia': A mixed-methods survey from Switzerland.

BACKGROUND AND HYPOTHESIS: This survey explores Swiss mental health professionals', users', and relatives' opinions on re-naming schizophrenia exploiting Switzerland's specific multilingualism to examine possible effects of linguistic and microcultural differences on the issue. STUDY DESIGN: Opinions on 'schizophrenia' were collected using a self-rated online questionnaire incl. Freetext answers available in the three main Swiss languages, German, French and Italian. It was distributed to the main professional and self-help organizations in Switzerland between June and October 2021. STUDY RESULTS: Overall, 449 persons completed the questionnaire, 263 in German, 172 in French and 14 in Italian. Of the total sample, 339 identified as mental health professionals, 81 as relatives and 29 as users. Considering the whole sample, almost half favored a name-change with a significant difference between stakeholder- and between language groups. Also, the name 'schizophrenia' was evaluated more critically than the diagnostic concept. Qualitative analysis of freetext answers showed a highly heterogenous argumentation, but no difference between language groups. CONCLUSIONS: Our results suggest the attitude towards re-naming might itself be subject to (micro)cultural difference, and they highlight the nature of 'schizophrenia' as not only a scientific, but also a linguistic and cultural object. Such local factors ought to be taken into consideration in the global debate.

"It's Tough to Be a Black Man with Schizophrenia": Randomized Controlled Trial of a Brief Video Intervention to Reduce Public Stigma.

BACKGROUND AND HYPOTHESIS: Racial discrimination and public stigma toward Black individuals living with schizophrenia create disparities in treatment-seeking and engagement. Brief, social-contact-based video interventions efficaciously reduce stigma. It remains unclear whether including racial identity experiences in video narrative yields greater stigma reduction. We hypothesized that we would replicate findings showing sustained stigma reduction in video-intervention groups vs control and that Black participants would show greater stigma reduction and emotional engagement than non-Black participants only for a racial-insights video presenting a Black protagonist. STUDY DESIGN: Recruiting using a crowdsourcing platform, we randomized 1351 participants ages 18-30 to (a) brief video-based intervention, (b) racial-insights-focused brief video, or (c) non-intervention control, with baseline, post-intervention, and 30-day follow-up assessments. In 2-minute videos, a young Black protagonist described symptoms, personal struggles, and recovery from schizophrenia, with or without mentioning race-related experiences. STUDY RESULTS: A 3 × 3 ANOVA showed a significant group-by-time interaction for total scores of each of five stigma-related domains: social distance, stereotyping, separateness, social restriction, and perceived recovery (all P < .001). Linear mixed modeling showed a greater reduction in stigma from baseline to post-intervention among Black than non-Black participants in the racial insights video group for the social distance and social restriction domains. CONCLUSIONS: This randomized controlled trial replicated and expanded previous findings, showing the anti-stigma effects of a brief video tailored to race-related experiences. This underscores the importance of personalized, culturally relevant narratives, especially for marginalized groups who, more attuned to prejudice and discrimination, may particularly value identification and solidarity. Future studies should explore mediators/moderators to improve intervention efficacy.

Ethnoracial Risk Variation Across the Psychosis Continuum in the US: A Systematic Review and Meta-Analysis.

Importance: Studies suggest a higher risk of schizophrenia diagnoses in Black vs White Americans, yet a systematic investigation of disparities that include other ethnoracial groups and multiple outcomes on the psychosis continuum is lacking. Objective: To identify ethnoracial risk variation in the US across 3 psychosis continuum outcomes (ie, schizophrenia and other psychotic disorders, clinical high risk for psychosis [CHR-P], and psychotic symptoms [PSs] and psychotic experiences [PEs]). Data Sources: PubMed, PsycINFO and Embase were searched up to December 2022. Study Selection: Observational studies on ethnoracial differences in risk of 3 psychosis outcomes. Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Using a random-effects model, estimates for ethnoracial differences in schizophrenia and PSs/PEs were pooled and moderation by sampling and setting was determined, along with the assessment of heterogeneity and risk of bias. Main Outcomes and Measures: Risk of schizophrenia and other psychotic disorder, CHR-P, and conversion to psychosis among CHR-P and PSs/PEs. Results: Of 64 studies in the systematic review, 47 were included in the meta-analysis comprising 54 929 people with schizophrenia and 223 097 with data on PSs/PEs. Compared with White individuals, Black individuals had increased risk of schizophrenia (pooled odds ratio [OR], 2.07; 95% CI, 1.64-2.61) and PSs/PEs (pooled standardized mean difference [SMD], 0.10; 95% CI, 0.03-0.16), Latinx individuals had higher risk of PSs/PEs (pooled SMD, 0.15; 95% CI, 0.08-0.22), and individuals classified as other ethnoracial group were at significantly higher risk of schizophrenia than White individuals (pooled OR, 1.81; 95% CI, 1.31-2.50). The results regarding CHR-P studies were mixed and inconsistent. Sensitivity analyses showed elevated odds of schizophrenia in Asian individuals in inpatient settings (pooled OR, 1.84; 95% CI, 1.19-2.84) and increased risk of PEs among Asian compared with White individuals, specifically in college samples (pooled SMD, 0.16; 95% CI, 0.02-0.29). Heterogeneity across studies was high, and there was substantial risk of bias in most studies. Conclusions and Relevance: Findings of this systematic review and meta-analysis revealed widespread ethnoracial risk variation across multiple psychosis outcomes. In addition to diagnostic, measurement, and hospital bias, systemic influences such as structural racism should be considered as drivers of ethnoracial disparities in outcomes across the psychosis continuum in the US.

Comparison of Black and white individuals who report diagnoses of schizophrenia in a national sample of US adults: Discrimination and service use.

BACKGROUND: While there is increasing recognition of disparities in healthcare for Black Americans, there have been no comparisons in a nationally representative U.S. sample of Black and White adults with clinical diagnoses of schizophrenia. METHODS: Using nationally representative survey data from the National Epidemiologic Survey on Alcohol and Related Conditions-III, we compared Black (n = 240, 36.2%) and White (n = 423, 63.8%) adults who report having been told by a physician that they have schizophrenia. Due to the large sample size, effect sizes (risk ratios and Cohen's d), rather than p-values, were used to identify the magnitude of differences in sociodemographic and clinical characteristics, including experiences of discrimination and service use. Multivariate analyses were used to identify independent factors. RESULTS: Black individuals with diagnoses of schizophrenia reported multiple sociodemographic disadvantages, including lower rates of employment, educational attainment, income, marriage, and social support, with little difference in incarceration, violent behavior, and quality of life. They reported much higher scores on a general lifetime discrimination scale (Cohen's d = 0.75) and subscales representing job discrimination (d = 0.85), health system discrimination (d = 0.70), and public race-based abuse (d = 0.55) along with higher rates of past year alcohol and drug use disorders, but lower rates of co-morbid psychiatric disorders. Multivariable-adjusted regression analyses highlighted the independent association of Black race with measures of discrimination and religious service attendance; less likelihood of receiving psychiatric treatment (p = 0.02) but no difference in substance use treatment. CONCLUSION: Black adults with schizophrenia report numerous social disadvantages, especially discrimination, but religious service attendance may be an important social asset.

Effect of CYP2C19 polymorphisms on serum valproic level acid in Chinese Han patients with schizophrenia.

Valproic acid is an anticonvulsant, which is also widely used for treating psychiatric disorders. Some clinical trials have demonstrated benefits of valproic acid augmentation therapy in schizophrenia. Interindividual variability in valproic acid dose and serum concentration may reflect functional consequences of genetic polymorphisms in genes encoding drug-metabolizing enzymes. The aim of this study was to determine the relationship between serum concentrations of valproic acid and single nucleotide polymorphisms of the cytochrome P450 (CYP) 2C19 gene in patients with schizophrenia. All patients had been receiving fixed dose of valproic acid for at least 2 weeks. The daily doses were 0.5-1.5 g. No other drugs except olanzapine were coadministered. Serum concentrations of valproic acid were measured using the ultra-high performance liquid chromatography method with mass-spectrometric detection. The CYP2C19 (CYP2C19*2 G681A rs4244285 and CYP2C19*3 G636A rs4986893) genotypes were identified by real-time PCR analyses. The mean concentration/dose ratios of valproic acid were significantly higher in patients with CYP2C19 *1/*2 genotype (P < 0.01) or CYP2C19 *2/*3 genotype (P < 0.01) than in those with CYP2C12 *1/*1 genotype. The mean concentration/dose ratios of valproic acid were significantly higher in patients with 1 (P < 0.01) or 2 (P < 0.01) mutated alleles for CYP2C19 than in those without mutated alleles. And the post hoc analysis revealed that the result has acceptable statistical (power (1 - ß) = 0.8486 at type I level of 0.05) to support the observed significant associations for CYP2C19 SNPs and serum C/D ratios of valproic acid. The findings of this study suggest that the genetic polymorphisms of CYP2C19 significantly affect the steady-state serum concentrations of valproic acid in Chinese Han population. The determination of the CYP2C19 genotypes may be useful for dosing adjustment in schizophrenia patients on valproic acid therapy.

Disproportionate increases in schizophrenia diagnoses among Black nursing home residents with ADRD.

BACKGROUND: Previous research demonstrated an increase in the reporting of schizophrenia diagnoses among nursing home (NH) residents after the Centers for Medicare & Medicaid Services National Partnership to Improve Dementia Care. Given known health and healthcare disparities among Black NH residents, we examined how race and Alzheimer's and related dementia (ADRD) status influenced the rate of schizophrenia diagnoses among NH residents following the partnership. METHODS: We used a quasi-experimental difference-in-differences design to study the quarterly prevalence of schizophrenia among US long-stay NH residents aged 65 years and older, by Black race and ADRD status. Using 2011-2015 Minimum Data Set 3.0 assessments, our analysis controlled for age, sex, measures of function and frailty (activities of daily living [ADL] and Changes in Health, End-stage disease and Symptoms and Signs scores) and behavioral expressions. RESULTS: There were over 1.2 million older long-stay NH residents, annually. Schizophrenia diagnoses were highest among residents with ADRD. Among residents without ADRD, Black residents had higher rates of schizophrenia diagnoses compared to their nonblack counterparts prior to the partnership. Following the partnership, Black residents with ADRD had a significant increase of 1.7% in schizophrenia as compared to nonblack residents with ADRD who had a decrease of 1.7% (p = 0.007). CONCLUSIONS: Following the partnership, Black NH residents with ADRD were more likely to have a schizophrenia diagnosis documented on their MDS assessments, and schizophrenia rates increased for Black NH residents with ADRD only. Further work is needed to examine the impact of "colorblind" policies such as the partnership and to determine if schizophrenia diagnoses are appropriately applied in NH practice, particularly for black Americans with ADRD.

NGS-based mtDNA Profiling Could Reveal Genetic Alterations in Schizophrenia.

BACKGROUND: Schizophrenia is a complex disease with a putative genetic background. It was hypothesized that impaired mitochondrial function due to genetic alterations in mitochondrial DNA (mtDNA) could contribute to neurological conditions, including mental disorders. The aim of the study was to find out possible pathogenic mutations and/or variants in mtDNA potentially related to schizophrenia development. OBJECTIVE: The study involved 37 patients with paranoid schizophrenia, whose mtDNA profiles were compared to those of 23 healthy controls. METHODS: Patients and controls were assessed using PANSS (Positive and Negative Syndrome Scale) and General Health Questionnaire (GHQ), respectively. The entire mtDNA was sequenced by the NGS platform (MiSeq®, Illumina). Bioinformatics data were processed by mtDNA Variant Processor and Analyser (Illumina), mtDNA-Server, and SPSS-17. RESULTS: A total of 480 mtDNA variants (single nucleotide replacements, point insertions, and deletions) were found. The polymorphic variant m.1811A>G (MT-RNR2) showed the highest frequency in schizophrenia (24.3%), as compared to the controls (4.3%) (p=0.07). Increased frequency was also found mainly in polymorphisms, belonging to complex 1 genes: MT-ND4 (11251G and 11467G), MT-ND3 (10398G), MT-ND1 (4216С), and MT-ND5 (12611G and 13708А), some of which were associated with mitochondrial dysfunction. Two individual mutations were identified in the patients: a pathogenic one - m.11778 A>G (LHON) and a newly identified, potentially pathogenic - m.4115 Т>C (NADH dehydrogenase 1). CONCLUSION: Particular mtDNA variants predominantly in complex I, probably serve as a risk genetic background in schizophrenia. The presence of pathogenic mutations in patients with psychotic manifestations expands the clinical scope of mitochondrial diseases and deserves further investigation.

Schizophrenia hospitalization in the US 2005-2014: Examination of trends in demographics, length of stay, and cost.

ABSTRACT: Primarily we aimed to examine the crude and standardized schizophrenia hospitalization trend from 2005 to 2014. We hypothesized that there will be a statistically significant linear trend in hospitalization rates for schizophrenia from 2005 to 2014. Secondarily we also examined trends in hospitalization by race/ethnicity, age, gender, as well as trends in hospitalization Length of Stay (LOS) and inflation adjusted cost.In this observational study, we used Nationwide Inpatient Sample data and International Classification of Diseases, Eleventh Revisions codes for Schizophrenia, which revealed 6,122,284 cases for this study. Outcomes included crude and standardized hospitalization rates, race/ethnicity, age, cost, and LOS. The analysis included descriptive statistics, indirect standardization, Rao-Scott Chi-Square test, t-test, and adjusted linear regression trend.Hospitalizations were most prevalent for individuals ages 45-64 (38.8%), African Americans were overrepresented (25.8% of hospitalizations), and the gender distribution was nearly equivalent. Mean LOS was 9.08 days (95% confidence interval 8.71-9.45). Medicare was the primary payer for most hospitalizations (55.4%), with most of the costs ranging from $10,000-$49,999 (57.1%). The crude hospitalization rates ranged from 790-1142/100,000 admissions, while the US 2010 census standardized rates were 380-552/100,000 from 2005-2014. Linear regression trend analysis showed no significant difference in trend for race/ethnicity, age, nor gender (P > .001). The hospitalizations' overall rates increased while LOS significantly decreased, while hospitalization costs and Charlson's co-morbidity index increased (P < .001).From 2005-2014, the overall US hospitalization rates significantly increased. Over this period, observed disparities in hospitalizations for middle-aged and African Americans were unchanged, and LOS has gone down while costs have gone up. Further studies addressing the important disparities in race/ethnicity and age and reducing costs of acute hospitalization are needed.

Ethnicity-dependent effects of Zinc finger 804A variant on schizophrenia: a systematic review and meta-analysis.

OBJECTIVES: Previous studies and meta-analysis indicated that rs1344706 was associated with schizophrenia in European population, whereas the conclusions in other populations were disputed. To further explore whether the allele A of rs1344706 would increase the risk of schizophrenia in different populations and update the original meta-analysis, we conducted a systematic review and meta-analysis worldwide. METHODS: A literature search was performed in PubMed, Embase, Cochrane Library, PsycINFO and Web of Science (up to 10 July 2019) according to the inclusion criteria. RESULTS: A total of 27 articles were included. Our meta-analysis showed an association between rs1344706 and schizophrenia in total populations [P = 0.000; odds ratio (OR) = 1.105; 95% confidence interval (CI), 1.048-1.165], Europe population (P = 0.025; OR = 1.108; 95% CI, 1.013-1.222) and Asian population(P = 0.005; OR = 1.094; 95% CI, 1.027-1.164). CONCLUSIONS: Our findings suggested that the risk of single nucleotide polymorphism rs1344706 A-allele may increase the risk of schizophrenia worldwide. Also, this ethnicity-dependent effects of ZNF804A variant on schizophrenia may be related to the opposite allele direction. But to elucidate the underlying biological mechanism, further studies with large participant populations are needed.

Social disadvantage, linguistic distance, ethnic minority status and first-episode psychosis: results from the EU-GEI case-control study.

BACKGROUND: Ethnic minority groups in Western countries face an increased risk of psychotic disorders. Causes of this long-standing public health inequality remain poorly understood. We investigated whether social disadvantage, linguistic distance and discrimination contributed to these patterns. METHODS: We used case-control data from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study, carried out in 16 centres in six countries. We recruited 1130 cases and 1497 population-based controls. Our main outcome measure was first-episode ICD-10 psychotic disorder (F20-F33), and exposures were ethnicity (white majority, black, mixed, Asian, North-African, white minority and other), generational status, social disadvantage, linguistic distance and discrimination. Age, sex, paternal age, cannabis use, childhood trauma and parental history of psychosis were included as a priori confounders. Exposures and confounders were added sequentially to multivariable logistic models, following multiple imputation for missing data. RESULTS: Participants from any ethnic minority background had crude excess odds of psychosis [odds ratio (OR) 2.03, 95% confidence interval (CI) 1.69-2.43], which remained after adjustment for confounders (OR 1.61, 95% CI 1.31-1.98). This was progressively attenuated following further adjustment for social disadvantage (OR 1.52, 95% CI 1.22-1.89) and linguistic distance (OR 1.22, 95% CI 0.95-1.57), a pattern mirrored in several specific ethnic groups. Linguistic distance and social disadvantage had stronger effects for first- and later-generation groups, respectively. CONCLUSION: Social disadvantage and linguistic distance, two potential markers of sociocultural exclusion, were associated with increased odds of psychotic disorder, and adjusting for these led to equivocal risk between several ethnic minority groups and the white majority.

Spontaneous and emergent extrapyramidal syndromes in Black Africans with first-episode schizophrenia and first exposure to antipsychotics.

BACKGROUND: Persons of African ancestry are thought to carry a higher risk for extrapyramidal syndromes (EPS) in schizophrenia. AIM: We investigated the phenomenon of spontaneous and treatment-emergent EPS in a sample comprising Xhosa (South Africa) and Yoruba (Nigeria) Africans with first-episode schizophrenia and first exposure to antipsychotics. METHODS: The Extrapyramidal Symptom Rating Scale (ESRS) and a variety of validated tools were used for the assessment of participants before, and two-weekly after treatment with low dose flupenthixol decanoate. Participants were followed up for 12 months. Association of EPS with clinical characteristics was investigated using Pearson's correlation and linear regression analyses. RESULTS: Of 88 participants at baseline, 16 (18.1%) had at least one definite EPS prior to antipsychotic exposure and 34 (38.6%) had treatment-emergent EPS. While spontaneous Parkinsonism was associated with negative symptoms (r = 0.2, p = 0.043; ß = 0.6, p = 0.043), treatment-emergent EPS demonstrated non-significant correlations with clinical characteristics. Apart from dyskinesia, the frequency of treatment-emergent EPS decreased over 12 months observation. CONCLUSION: These findings support the hypothesis suggesting that spontaneously occurring Parkinsonism in schizophrenia may be the motor spectrum of negative symptomatology. Future studies of this relationship may lead to early identification of patients who may be more sensitive to EPS.

Association Between REELIN Gene Polymorphisms (rs7341475 and rs262355) and Risk of Schizophrenia: an Updated Meta-analysis.

Schizophrenia (SCZ) is a destructive neuropsychiatric illness affecting millions of people worldwide. The correlation between RELN gene polymorphisms and SCZ was investigated by previous researches, though the results remained conflicting. Based on the available studies, we conducted this meta-analysis to provide a more comprehensive outcome on whether the RELN gene polymorphisms (rs7341475 and rs262355) are associated with SCZ. A total of 15 studies with 25,403 subjects (9047 cases and 16,356 controls) retrieved from PubMed, ScienceDirect, EMBASE, Wiley, BMC, Cochrane, Springer, MDPI, SAGE, and Google Scholar up to June 2020 were included. Meta-analysis was performed using Review Manager 5.3. The heterogeneity was checked using I2 statistics and Q-test, whereas publication bias was also measured. The rs7341475 polymorphism showed a significantly lower risk for SCZ for the allele (A vs. G: OR = 0.93, 95%CI = 0.87-0.99), codominant 1 (AG vs. GG: OR = 0.92, 95%CI = 0.85-0.99), dominant model (AA+AG vs. GG: OR = 0.92, 95%CI = 0.86-0.98), and over dominant model (AG vs. AA+GG: OR = 0.92, 95%Cl = 0.86-0.99). The allele, codominant model 1, and dominant models remained statistically significant after the correction of the Bonferroni (p < 0.025). Subgroup analysis confirmed the association of allele and dominant models in the Caucasian after Bonferroni correction. For rs262355 polymorphism, a significantly increased risk of SCZ was found only in Caucasians for codominant 2, dominant, and allele models, but significance exists only for the allele model after Bonferroni correction. Publication bias was found in the case of codominant 2 and recessive models for rs7341475 in the overall population, but this publication was not found after performing the Bonferroni correction or after performing the subgroup analysis. No such publication was found for rs262355. The results suggest that RELN rs7341475 is associated with a lower risk of SCZ in the overall population and Caucasian population, but rs262355 is associated with an increased risk of SCZ only in the Caucasian population.

Identification of SHANK2 Pathogenic Variants in a Chinese Uygur Population with Schizophrenia.

Genomic studies on schizophrenia (SCZ) have revealed several candidate genes involved in excitatory synapse function and plasticity associated with its etiology. SHANK2 is a postsynaptic scaffolding protein, which anchors a protein complex connecting NMDAR, AMPAR, and mGluR receptors at excitatory neuronal synapses. Mutations in the SHANK2 gene have been reported to be associated with human autism spectrum disorders (ASDs) and SCZ. To identify variants in the SHANK2 gene and determine the association of SHANK2 with SCZ in the Chinese Uygur population, we conducted targeted sequencing of whole exon regions and exon-intron boundaries of SHANK2 in 1574 SCZ patients and 1481 healthy controls. A total of 149 variants were identified, including six common variants and 143 rare variants. For common variants, rs62622853 and rs3924047 showed allelic significance with SCZ before correction, but the association was eliminated after Bonferroni correction. Seven rare nonsynonymous variants, p.Arg739Trp, p.Pro807Leu, p.Ile854Phe, p.Thr1322Ser, p.Leu1434Arg, p.Val1486Ile, and p.Thr1674Met, occurred only in the patients but not in any of the healthy controls. In silico analysis predicted that p.Arg739Trp, p.Leu1434Arg, and p.Val1486Ile variants are likely to be damaging. The present study suggests that individuals with two novel rare nonsynonymous variants (p.Arg739Trp, p.Leu1434Arg) and p.Val1486Ile variants of SHANK2 might increase the susceptibility to developing SCZ disorder.

Methylome-wide association study of first-episode schizophrenia reveals a hypermethylated CpG site in the promoter region of the TNIK susceptibility gene.

Accumulating evidence suggests that epigenetics plays an important role in the etiology of schizophrenia. Here, we performed a methylome-wide association study (MWAS) of first-onset schizophrenia patients and controls from the Han Chinese population using microarray technology. The DNA methylation profiles revealed 4494 differentially methylated CpG sites. Gene ontology (GO) analysis showed that the functions of differentially methylated genes were primarily involved in enzymatic activity, cytoskeleton organization and cell adhesion, and the TNIK (encoding TRAF2- and NCK-interacting kinase) gene was enriched in most of these terms. By combining the MWAS results with those of previous genome-wide association studies (GWASs), we identified 72 candidate genes located in 49 human genome loci. Among the overlapping genes, the most significantly methylated CpG sites were in the transcriptional start site (TSS) 200 region (cg21413905, Punadjusted = 3.20 × 10-5) of TNIK. TNIK was listed in the top 50 differentially methylated loci. The results of pyrosequencing and TNIK mRNA expression were consistent with those of the microarray study. Bioinformatics analyses, dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP) studies showed that TNIK interacted with genes associated with schizophrenia and NRF1 was identified as a novel transcription factor (TF) that binds to TNIK in its TSS200 region. Thus, the regulatory function of NRF1 may be influenced by the status of the methylated CpG site in this region. In summary, our study provides new insights into the epigenetic mechanisms that regulate schizophrenia. Studies of the functions of TNIK methylation should be performed in vitro and in vivo to provide a better understanding of the pathophysiology of schizophrenia.

A Human-Specific Schizophrenia Risk Tandem Repeat Affects Alternative Splicing of a Human-Unique Isoform AS3MTd2d3 and Mushroom Dendritic Spine Density.

Recent advances in functional genomics have facilitated the identification of multiple genes and isoforms associated with the genetic risk of schizophrenia, yet the causal variations remain largely unclear. A previous study reported that the schizophrenia risk single-nucleotide polymorphism (SNP) rs7085104 at 10q24.32 was in high linkage disequilibrium (LD) with a human-specific variable number of tandem repeat (VNTR), and both were significantly associated with the brain mRNA expression of a human-unique AS3MTd2d3 isoform in Europeans and African Americans. In this study, we have shown the direct regulation of the AS3MTd2d3 mRNA expression by this VNTR through an in vitro minigene splicing assay, suggesting that it is likely a causative functional variation. Intriguingly, we have further confirmed that the VNTR and rs7085104 are significantly associated with AS3MTd2d3 mRNA expression in brains of Han Chinese donors, and rs7085104 is also associated with risk of schizophrenia in East Asians. Finally, the overexpression of AS3MTd2d3 in cultured primary hippocampal neurons results in significantly reduced densities of mushroom dendritic spines, implicating its potential functional impact. Considering the crucial roles of dendritic spines in neuroplasticity, these results reveal the potential regulatory impact of the schizophrenia risk VNTR on AS3MTd2d3 and provide insights into the underlying biological mechanisms.

Schizophrenia risk candidate EGR3 is a novel transcriptional regulator of RELN and regulates neurite outgrowth via the Reelin signal pathway in vitro.

Schizophrenia is a severe psychiatric disorder with a strong hereditary component that affects approximately 1% of the world's population. The disease is most likely caused by the altered expression of a number of genes that function at the level of biological pathways or gene networks. Transcription factors (TF) are indispensable regulators of gene expression. EGR3 is a TF associated with schizophrenia. In the current study, DNA microarray and ingenuity pathway analyses (IPA) demonstrated that EGR3 regulates Reelin signaling pathway in SH-SY5Y cells. ChIP and luciferase reporter studies confirmed that EGR3 directly binds to the promoter region of RELN thereby activating RELN expression. The expression of both EGR3 and RELN was decreased during neuronal differentiation induced by retinoic acid (RA) in SH-SY5Y cells, and EGR3 over-expression reduced neurite outgrowth which could be partially reversed by the knockdown of RELN. The expression levels of EGR3 and RELN in peripheral blood of subjects with schizophrenia were found to be down-regulated (compared with healthy controls), and were positively correlated. Furthermore, data mining from public databases revealed that the expression levels of EGR3 and RELN were presented a positive correlation in post-mortem brain tissue of subjects with schizophrenia. Taken together, this study suggests that EGR3 is a novel TF of the RELN gene and regulates neurite outgrowth via the Reelin signaling pathway. Our findings contribute to the understanding of the regulatory role of EGR3 in the pathophysiology and molecular mechanisms of schizophrenia, and potentially to the development of new therapies and diagnostic biomarkers for the disorder.

Association of family history of schizophrenia and history of obstetric complications at birth: relationship with age at onset and psychopathology dimensions in a Nigerian cohort.

BACKGROUND: The nature of the association between obstetric complications (OCs) at birth and the genetic aetiology of schizophrenia remains unclear, as some authors suggest that it is an independent risk factor while others support either interactionism or an epiphenomenon perspective. OBJECTIVE: To examine the association of family history of schizophrenia (FHS) with history of OCs, with a view to assessing whether this relationship moderates clinical phenotypes such as symptom dimensions and age at onset of illness. METHODS: This study examined OCs among schizophrenia probands using the Obstetric Complications Scale. An inquiry into family history was performed using the Family history method. Psychopathological symptom dimensions were assessed using standard scales. Data were analyzed to examine the interaction of FHS and history of OCs with age at onset and symptom dimensions, using ANCOVA. RESULTS: FHS was significantly associated with the disorganized symptoms dimension (p=0.03). History of OCs was significantly associated with earlier age at onset (p=0.007). However, in ANCOVA, the effect of the interaction between FHS and history of OCs was not significant for age at onset and symptom dimensions (P = 0.059). CONCLUSION: FHS was significantly associated with disorganization syndrome, and OCs was significantly associated with age at onset.

Exploring Similarities and Differences of Non-European Migrants among Forensic Patients with Schizophrenia.

Migrants diagnosed with schizophrenia are overrepresented in forensic-psychiatric clinics. A comprehensive characterization of this offender subgroup remains to be conducted. The present exploratory study aims at closing this research gap. In a sample of 370 inpatients with schizophrenia spectrum disorders who were detained in a Swiss forensic-psychiatric clinic, 653 different variables were analyzed to identify possible differences between native Europeans and non-European migrants. The exploratory data analysis was conducted by means of supervised machine learning. In order to minimize the multiple testing problem, the detected group differences were cross-validated by applying six different machine learning algorithms on the data set. Subsequently, the variables identified as most influential were used for machine learning algorithm building and evaluation. The combination of two childhood-related factors and three therapy-related factors allowed to differentiate native Europeans and non-European migrants with an accuracy of 74.5% and a predictive power of AUC = 0.75 (area under the curve). The AUC could not be enhanced by any of the investigated criminal history factors or psychiatric history factors. Overall, it was found that the migrant subgroup was quite similar to the rest of offender patients with schizophrenia, which may help to reduce the stigmatization of migrants in forensic-psychiatric clinics. Some of the predictor variables identified may serve as starting points for studies aimed at developing crime prevention approaches in the community setting and risk management strategies tailored to subgroups of offenders with schizophrenia.

Gender difference in the association between education and schizophrenia in Chinese adults.

BACKGROUND: Improving education level was evidenced to decrease the risk of schizophrenia, but whether this strength of education role depends on gender is not. This study aimed to investigate whether there was gender difference in the association between education and schizophrenia in Chinese adults. METHODS: Data were obtained from the Second China National Sample Survey on Disability in 2006, including 1,909,205 participants aged 18 years or older. Schizophrenia was ascertained according to the International Statistical Classification of Diseases, Tenth Revision. Logistics regression models were fitted to examine the combined effect of gender and education on schizophrenia. RESULTS: The lifetime prevalence of schizophrenia in female groups was higher than in male groups, with 0.44% (95%CI: 0.42-0.45%) and 0.36% (95%CI: 0.35-0.37%), respectively. Compared with schizophrenia male patients, more females with schizophrenia experienced severe or extreme difficulty in understanding and communicating. However, more males with schizophrenia suffered from severe or extreme difficulty in the function of daily activities. The combined effect of education and schizophrenia was statistically significant, indicating that, as the level of education increased, schizophrenia risk of females decreased faster than the risk of males. CONCLUSIONS: This study showed that additional years of education associated with lower risk of schizophrenia, and this association was stronger in females than in males. As education elevated, the risk of schizophrenia decreased more for women than for men. The findings indicate that improving education level may have an effect on reducing the gender disparities in mental health of China. Actions to prevent schizophrenia and address its gender disparities will require attention to the improving educational opportunities.