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Detailed analyses of transcriptome have revealed complexity in regulation of alternative splicing (AS). These AS events often undergo modulation by genetic variants. Here we analyse RNA-sequencing data of prefrontal cortex from 206 individuals in combination with their genotypes and identify cis -acting splicing quantitative trait loci (sQTLs) throughout the genome. These sQTLs are enriched among exonic and H3K4me3-marked regions. Moreover, we observe significant enrichment of sQTLs among disease-associated loci identified by GWAS, especially in schizophrenia risk loci. Closer examination of each schizophrenia-associated loci revealed four regions (each encompasses NEK4 , FXR1 , SNAP91 or APOPT1 ), where the index SNP in GWAS is in strong linkage disequilibrium with sQTL SNP(s), suggesting dysregulation of AS as the underlying mechanism of the association signal. Our study provides an informative resource of sQTL SNPs in the human brain, which can facilitate understanding of the genetic architecture of complex brain disorders such as schizophrenia. Alternative splicing of mRNAs occurs in tissue specific manners and may be modulated by genetic variations. Here, Takata and colleagues perform splicing quantitative trait loci analysis (sQTL) of human brain and show significant enrichment of sQTLs among neurological disease-associated loci.

Psychiatric disorders such as schizophrenia and bipolar disorder are caused by complex gene–environment interactions. While recent advances in genomic technologies have enabled the identification of several risk variants for psychiatric conditions, including single-nucleotide variants and copy-number variations, these factors can explain only a portion of the liability to these disorders. Although non-inherited factors had previously been attributed to environmental causes, recent genomic analyses have demonstrated that de novo mutations are among the main non-inherited risk factors for several psychiatric conditions. Somatic mutations in the brain may also explain how stochastic developmental events and environmental insults confer risk for a psychiatric disorder following fertilization. Here, we review evidence regarding somatic mutations in the brains of individuals with and without neuropsychiatric diseases. We further discuss the potential biological mechanisms underlying somatic mutations in the brain as well as the technical issues associated with the detection of somatic mutations in psychiatric research.

Ntrk1 (also known as TrkA) is a nerve growth factor receptor with essential roles in the development and function of the cholinergic nervous system. Ntrk1 is expressed in a few specific and defined brain areas. Specific antibodies are necessary to identify the expression and localization of Ntrk1 in the brain, and validating signal authenticity is critical. These issues have not been investigated sufficiently. We evaluated the utility of commercial antibodies for Ntrk1 using western blotting in brain lysates from Ntrk1 knockout mice and tested the utility of the antibody that showed specificity in western blotting for immunohistochemistry applications in the adult mouse brain. We confirmed specificity for one of the seven commercial antibodies in western blots, in which the specific bands were absent in the knockout samples. Using this antibody, we performed immunohistochemical staining of the brain tissues of adult mice to examine Ntrk1 localization. Distinct signals were observed in regions with known Ntrk1 expression, such as the striatum and basal forebrain. The characteristic expression pattern of Ntrk1 in the paraventricular thalamic nucleus (PVT) was verified at the protein level, with high and low expression levels in the anterior and posterior PVT, respectively.

Melatonin is a pineal hormone produced at night; however, many strains of laboratory mice are deficient in melatonin. Strangely enough, the gene encoding HIOMT enzyme (also known as ASMT) that catalyzes the last step of melatonin synthesis is still unidentified in the house mouse (Mus musculus) despite the completion of the genome sequence. Here we report the identification of the mouse Hiomt gene, which was mapped to the pseudoautosomal region (PAR) of sex chromosomes. The gene was highly polymorphic, and nonsynonymous SNPs were found in melatonin-deficient strains. In C57BL/6 strain, there are two mutations, both of which markedly reduce protein expression. Mutability of the Hiomt likely due to a high recombination rate in the PAR could be the genomic basis for the high prevalence of melatonin deficiency. To understand the physiologic basis, we examined a wild-derived strain, MSM/Ms, which produced melatonin more under a short-day condition than a long-day condition, accompanied by increased Hiomt expression. We generated F2 intercrosses between MSM/Ms and C57BL/6 strains and N2 backcrosses to investigate the role of melatonin productivity on the physiology of mice. Although there was no apparent effect of melatonin productivity on the circadian behaviors, testis development was significantly promoted in melatonin-deficient mice. Exogenous melatonin also had the antigonadal action in mice of a melatonin-deficient strain. These findings suggest a favorable impact of melatonin deficiency due to Hiomt mutations on domestic mice in breeding colonies.

Bipolar disorder (BD) is a severe mental disorder characterized by repeated mood swings. Although genetic factors are collectively associated with the etiology of BD, the underlying molecular mechanisms, particularly how environmental factors affect the brain, remain largely unknown. We performed promoter-wide DNA methylation analysis of neuronal and nonneuronal nuclei in the prefrontal cortex of patients with BD (N = 34) and controls (N = 35). We found decreased DNA methylation at promoters in both cell types in the BD patients. Gene Ontology (GO) analysis of differentially methylated region (DMR)-associated genes revealed enrichment of molecular motor-related genes in neurons, chemokines in both cell types, and ion channel- and transporter-related genes in nonneurons. Detailed GO analysis further revealed that growth cone- and dendrite-related genes, including NTRK2 and GRIN1, were hypermethylated in neurons of BD patients. To assess the effect of medication, neuroblastoma cells were cultured under therapeutic concentrations of three mood stabilizers. We observed that up to 37.9% of DMRs detected in BD overlapped with mood stabilizer-induced DMRs. Interestingly, mood stabilizer-induced DMRs showed the opposite direction of changes in DMRs, suggesting the therapeutic effects of mood stabilizers. Among the DMRs, 12 overlapped with loci identified in a genome-wide association study (GWAS) of BD. We also found significant enrichment of neuronal DMRs in the loci reported in another GWAS of BD. Finally, we performed qPCR of DNA methylation-related genes and found that DNMT3B was overexpressed in BD. The cell-type-specific DMRs identified in this study will be useful for understanding the pathophysiology of BD.

•We evaluated gray and white matter microstructure alterations using diffusion kurtosis imaging, free-water imaging, and neurite orientation dispersion and density imaging, in 28 patients with euthymic BD and 28 healthy controls.•We detected microstructure alterations in wide areas of white matter and gray matter in patients with BD.•In BD, cognitive function was correlated with gray matter microstructure alterations, reflected by increased extracellular FW in relevant brain areas, more strongly than with white matter impairment according to decreased FA. Bipolar disorder (BD) is a chronic mental disorder involving cognitive dysfunction. Imaging studies reveal reduced cortical thickness and impaired white matter integrity in BD; however, the biological pathophysiology underlying cognitive dysfunctions remains unclear. In 28 patients with euthymic BD and 28 healthy controls, we evaluated gray and white matter microstructure alterations using diffusion kurtosis imaging, free-water imaging, and neurite orientation dispersion and density imaging. We detected microstructure alterations using tract-based spatial statistics (TBSS) analysis and gray matter-based spatial statistics (GBSS). Voxel-wise analysis was performed to evaluate associations between microstructure alterations and cognitive performance measured by WAIS-IV. Compared to healthy controls, BD patients exhibited decreased fractional anisotropy (FA) and free-water (FW)-corrected FA, along with mean diffusivity (MD) and radial diffusivity (RD) across a wide area on TBSS. BD patients showed increased diffusion tensor imaging (DTI) indices, accompanied by increased isotropic volume fraction (ISOVF) and free-water (FW) in the frontal, temporal, parietal, and limbic areas on GBSS. The working memory index was negatively correlated with FW in the right hemisphere of the posterior corona radiata, and processing speed index was negatively correlated with FW in the bilateral isthmus of the cingulate gyrus, bilateral cerebellum cortex, parahippocampal gyrus, left hemisphere entorhinal cortex, and precuneus. Cognitive performance showed negligible correlations with DTI indices. In BD, cognitive function was correlated with gray matter microstructure alterations, reflected by increased extracellular FW in relevant brain areas, more strongly than with white matter impairment according to decreased FA.

Despite extensive genetic and neuroimaging studies, detailed cellular mechanisms underlying schizophrenia and bipolar disorder remain poorly understood. Recent progress in single-cell RNA sequencing (scRNA-seq) technologies enables identification of cell-type-specific pathophysiology. However, its application to psychiatric disorders is challenging because of methodological difficulties in analyzing human brains and the confounds due to a lifetime of illness. Brain organoids derived from induced pluripotent stem cells (iPSCs) of the patients are a powerful avenue to investigate the pathophysiological processes. Here, we generated iPSC-derived cerebral organoids from monozygotic twins discordant for psychosis. scRNA-seq analysis of the organoids revealed enhanced GABAergic specification and reduced cell proliferation following diminished Wnt signaling in the patient, which was confirmed in iPSC-derived forebrain neuronal cells. Two additional monozygotic twin pairs discordant for schizophrenia also confirmed the excess GABAergic specification of the patients’ neural progenitor cells. With a well-controlled genetic background, our data suggest that unbalanced specification of excitatory and inhibitory neurons during cortical development underlies psychoses.

Background Schizophrenia places a great humanistic and financial burden to patients, families, and societies, and the burden is substantially impacted by comorbid conditions. This study aimed to estimate the lifetime prevalence of schizophrenia and to assess the health-related quality of life (HRQoL), work productivity, and indirect cost among schizophrenia patients with and without comorbidities (depressive symptoms, sleep disturbances, and anxiety problems). Methods This is a secondary analysis of existing data collected in 2019 from the Japan National Health and Wellness Survey. The schizophrenia patients were categorized based on their Patient Health Questionnaire-9 score, self-reported experience of sleep disturbances, and anxiety problems. The lifetime prevalence was estimated using the total number of diagnosed schizophrenia patients as the numerator and the total number of respondents as the denominator. The HRQoL was evaluated through the Short Form 12-Item (version 2) Health Survey and EuroQoL 5-dimensions scale. Work productivity and annual indirect costs were evaluated through the Work Productivity and Activity Impairment instrument and monthly wage rates. Multivariate analyses included the comparison of outcomes using generalized linear models. Results The study was conducted with 178 schizophrenia patients with an average age of 42.7 years old and an estimated lifetime prevalence of 0.59% (95% CI: 0.51%, 0.68%). Patients who experienced sleep disturbances, more severe depressive symptoms, and anxiety problems had lower HRQoL, higher levels of absenteeism, presenteeism, total work productivity and activity impairment, and almost twice more indirect costs, compared to those without these conditions. Conclusion Comorbid conditions among patients with schizophrenia impact significantly on their quality of life, work productivity as well as indirect costs.