AIM:To establish and characterize neuropsychiatric manifestations of post-COVID-19 condition (PCC) through Japan's first nationwide registry integrating clinical assessments with patient-reported outcomes. METHODS:The Psychiatric Symptoms for COVID-19 Registry Japan collected data between December 2022 and September 2024, integrating electronic patient-reported outcomes (n = 806) with in-person clinical assessments (n = 136). Participants were classified as cases or tolerant controls following WHO criteria. The Composite Psychological Burden Score (CPBS) was constructed using principal component analysis of depression, anxiety, insomnia, cognitive dysfunction, and quality of life measures (accounting for 75.4% of variance). Sex-stratified multivariate analyses examined risk factors. RESULTS:Clinical evaluation revealed neurological symptoms (34.1%) as predominant manifestations, followed by pain-related symptoms (23.5%). PCC cases showed significantly higher rates of physical and psychiatric comorbidities, impaired quality of life, and work discontinuation (52.9%). Patient-reported perception of significant life changes due to PCC was most strongly associated with physician-diagnosed PCC (odds ratio [OR]: 11.2), followed by CPBS (OR: 6.25 per standard deviation, 95% CI: 2.48-15.7). Longer COVID-19 infection duration, unemployment, and reduced family communication were significant in both sexes. In sex-stratified analyses, psychiatric comorbidity (adjusted OR [aOR]: 5.68) and single status (aOR: 4.46) were significant in men and reduced outdoor activity in women (aOR up to 12.6); however, no interaction with sex reached significance, indicating that these sex differences were not statistically confirmed. CONCLUSION:Integrating subjective disease perception with psychological, cognitive, and quality of life measures may improve identification of neuropsychiatric burden in PCC. The sex-stratified patterns warrant confirmation in larger cohorts.

ABSTRACT Aim COVID‐19 has been associated with dysregulated immune responses, with increasing evidence indicating sustained inflammasome activation and subsequent pro‐inflammatory cytokine production. This study aimed to characterize the temporal profile of inflammatory markers, particularly interleukin (IL)‐1β, in post‐COVID‐19 patients compared with pre‐pandemic healthy controls, using data from the Psychiatric Symptoms for COVID‐19 Registry Japan (PSCORE‐J). Methods Blood samples were analyzed from 119 post‐COVID‐19 patients (median age 45 years) recruited during 2023 and 374 pre‐pandemic healthy controls (median age 65 years). For post‐COVID‐19 patients, samples were collected at baseline, 3 months, and 9 months. Multiple inflammatory markers were assessed, including IL‐1β, IL‐6, IL‐8, IL‐10, IL‐12, TNF‐α, IFN‐γ, IFN‐β, IP‐10, ACE2, and eotaxin. Age‐ and sex‐adjusted analyses were performed on log‐transformed IL‐1β levels. Results IL‐1β levels were significantly elevated in post‐COVID‐19 patients compared with healthy controls across all age groups (under 30s: 0.69 ± 0.33 vs. 0.25 ± 0.03; 30s: 0.70 ± 0.63 vs. 0.26 ± 0.09; 40s: 0.84 ± 0.76 vs. 0.30 ± 0.23; 50s: 0.67 ± 0.65 vs. 0.26 ± 0.10; 60 or over: 0.54 ± 0.30 vs. 0.26 ± 0.23 pg/mL). This elevation was sustained throughout the 9‐month follow‐up (baseline: 0.500 [0.33–0.890]; 3 months: 0.630 [0.28–1.290]; 9 months: 0.54 [0.29–0.96] pg/mL) compared with controls (0.24 [0.21–0.27] pg/mL). Other inflammatory markers showed either no significant differences or were paradoxically lower in patients. Conclusion SARS‐CoV‐2 infection is associated with persistent elevation of IL‐1β levels that remains stable over a 9‐month period, suggesting sustained inflammasome activation. These findings provide novel insight into post‐COVID‐19 inflammatory processes and may have important implications for understanding both acute and chronic manifestations of the disease. Trial Registration Japan Registry of Clinical Trials: jRCT1030220711

Background Recent studies have reported association between schizophrenia polygenic risk scores (PRS) and psychotropic medication usage in patients with psychotic disorders. Given the genetic correlation between psychotic disorders, we examined the relationship between PRS for SCZ, BD, and major depressive disorder (MDD) and the defined daily dose (DDD) of psychotropic medications in Japanese BD patients. Methods We retrospectively analyzed data from approximately 900 Japanese BD patients at Fujita Health University and Nagoya University. Prescription data was obtained from medical records, identifying the maximum dosage prescribed during outpatient visits. DDDs for psychotropic medications were calculated according to WHO standards. PRS for SCZ, BD, and MDD were computed using summary statistics from the Psychiatric Genomics Consortium GWASs. Multiple regression analyses were conducted to assess the association between DDD and PRS, age, sex, diagnosis subtype, and psychotic symptoms. Results In Japanese BD patients (n ≈ 900), schizophrenia PRS based on East Asian GWAS data was significantly positively associated with antipsychotic dosage. In contrast, no significant association was observed between bipolar disorder PRS and the dosage of antipsychotics or mood stabilizers. Stratified analysis by East Asian schizophrenia PRS quintiles showed that patients in the top 20% had significantly higher antipsychotic DDDs compared to those in the bottom 20%, with a mean difference of approximately 1.1 DDDs among those prescribed antipsychotics (n ≈ 400). Discussion These findings indicate that schizophrenia PRS is significantly associated with antipsychotic use in BD patients. This suggests that antipsychotic treatment may be more recommendable in BD patients with high schizophrenia PRS. Interestingly, BD PRS showed no significant association with medication dosage, highlighting that schizophrenia PRS may better capture the biological dimension relevant to antipsychotic treatment in BD. Our results support the genetic overlap between BD and SCZ and emphasizes the potential utility of PRS in guiding individualized treatment strategies in BD.

Background:Although neuronal dysfunction has been the focus of many studies on psychiatric disorders, accumulating evidence suggests that white matter abnormalities and oligodendrocyte lineage cells, including oligodendrocyte precursor cells (OPCs), play an important role. Beyond their established contribution to myelination, synaptic genes in OPCs form connections to neurons and influence neuronal circuits and plasticity, thereby potentially contributing to psychiatric pathology. Methods:We analyzed publicly available single-nucleus RNA sequencing (snRNA-seq) data from white matter cells of healthy donors with SCZ genome-wide association study (GWAS) summary statistics. We assessed cell-type-specific enrichment of SCZ-associated genetic variants and performed weighted gene co-expression network analysis (WGCNA) to identify disease-related gene modules in implicated cell types. Results:OPCs exhibited significant enrichment of SCZ-associated genetic risk variants and showed pronounced specificity in gene expression patterns. Through WGCNA, we identified a distinct co-expression module in OPCs that was enriched for synaptic genes associated with SCZ. Conclusion:The present results highlight the previously underappreciated role of OPCs in psychiatric disorders, suggesting that OPC-involved synaptic interactions may contribute to the pathophysiology of SCZ. This work underscores the importance of considering OPCs as active players in neural network dysfunction, with potential implications for future therapeutic strategies.

Background Antidepressant treatment response in major depressive disorder (MDD) varies substantially between individuals and remains difficult to predict prior to treatment. This individual variability has been estimated to have approximately 40% SNP-based heritability 1, indicating a considerable contribution from environmental factors. For traits with strong environmental influences, genome-wide association studies (GWAS) in ancestrally homogeneous populations are advantageous due to differences in cultural background, as well as linkage disequilibrium structure and allele frequency. In the present study, we conducted a GWAS using longitudinal data on antidepressant treatment response in a Japanese population. Methods Longitudinal clinical data were collected from 854 untreated patients with MDD, diagnosed according to DSM-IV or DSM-5 criteria, who underwent 4 weeks of antidepressant treatment Kansai Medical University Hospital and affiliates institutions. Genotyping was performed using the Illumina Asian Screening Array v1.0 (ASA; n = 516) and the Japanese Screening Array v1.0 (JSA; n = 338). Standard quality control (QC) procedures were applied, including filters for Hardy-Weinberg equilibrium (P < 1 × 10⁻⁷), call rate, MAF < 1%, sex chromosome variants, relatedness (PIHAT ≥ 0.5), and ancestry outliers based on 1000 Genomes PCA. After QC, 355 ASA and 329 JSA samples were retained. These were combined with the 135 later-genotyped ASA samples and processed through the same QC pipeline, resulting in 816 MDD cases and 352,724 variants. From this dataset, 223 patients treated with SSRIs monotherapy (including vortioxetine) and 106 treated with mirtazapine monotherapy were selected. For each group, SNPs with MAF < 5% were excluded, resulting in 259,759 and 265,051 variants, respectively. All QC steps were conducted using PLINK v1.9. To assess genetic effects on treatment response, GWAS was performed using generalized estimating equations (GEE), modeling change in 17-item Hamilton Depression Rating Scale (ΔHAMD) scores from baseline (week 0) to weeks 2 and 4. GEE models included individual IDs as clusters, weeks as repeated measures, an AR(1) correlation structure, and covariates: sex, age, and baseline HAMD score. Analyses were performed using the geepack package in R. The study protocol was approved by the relevant institutional review board and conducted in accordance with the Declaration of Helsinki for human research. Written informed consent was obtained from all participants. Results For SSRI longitudinal treatment response, top SNPs were located in CBFA2T3(P=6.2 × 10-9) and VIT(P=4.6 × 10-7), genes previously implicated in psychiatric traits. These variants exhibited additive effects across the 0-4 week periods. For Mirtazapine, top signals included SNPs within the LINC01982 locus (P=4.5 × 10-8), previously implicated in GWAS meta-analyses of treatment-resistant depression (P=4.77 × 10-6). Discussion This study represents the largest GWAS of antidepressant treatment response in MDD using longitudinal data exclusively from a Japanese population. Although the sample size remains small, SNPs on CBFA2T3 and VIT, and the LINC01982 locus may be involved in treatment response to SSRIs and mirtazapine, respectively. Given that many of the top signals had minor allele frequencies close to 5%, the possibility of false positives remains, and additional validation analyses are currently underway. Final results and interpretation will be presented at the conference.

OBJECTIVE:Levetiracetam (LEV) has been widely used as an antiseizure medication (ASM), but is associated with psychiatric and behavioral adverse effects (PBAEs). Brivaracetam (BRV) has demonstrated better psychiatric tolerability, albeit at a higher cost. This study aimed to evaluate the cost-effectiveness of initiating BRV versus LEV therapy with a subsequent switch to BRV in the event of PBAEs across the US, Australia, and Japan. METHODS:We developed a decision tree model with a 10-year time horizon comparing two strategies across the US, Australia, and Japan: initial BRV therapy versus initial LEV therapy with a switch to BRV upon the occurrence of PBAEs. We utilized clinical trial data and regional cost estimates to conduct base-case and probabilistic sensitivity analyses. RESULTS:The results of the base-case analyses indicated that initial BRV therapy was cost-effective only in Australia. The results of the sensitivity analyses revealed that the probability of initial BRV being cost-effective was 0% in the US, 49.6% in Japan, and 99.99% in Australia. In Japan, when the risk of LEV-induced PBAEs was assumed to be 24%, the probability that initial BRV therapy would be cost-effective rose to 70%, supporting the potential utility of an initial BRV strategy in high-risk populations. By contrast, in the US, the risk of PBAEs needed to exceed 76% to achieve a comparable cost-effectiveness probability. SIGNIFICANCE:While the initial BRV strategy consistently demonstrated cost-effectiveness in Australia, it failed to do so in Japan and the US. However, Japan presents a unique opportunity where BRV can be used cost-effectively when combined with pre-assessments of LEV-induced risk for PBAEs. PLAIN LANGUAGE SUMMARY:BRV causes fewer PBAEs than LEV, but costs more, creating a clinical dilemma. A cost-effectiveness analysis comparing BRV versus LEV as initial monotherapy with a focus on PBAEs was conducted across the US, Australia, and Japan. The results indicated that compared with LEV, BRV is cost-effective in Australia, but not in the US. In Japan, BRV is cost-effective as initial treatment only for patients at high risk for LEV-induced PBAEs.

Background Major depressive disorder (MDD) is a common psychiatric condition with a lifetime prevalence 10%. Its estimated heritability is about 40%, lower than that of schizophrenia or bipolar disorder, suggesting greater influence of environmental factors. For phenotypes significantly influenced by environmental components, genome-wide association studies (GWAS) in ancestrally homogeneous populations are preferred due to differences in racial and cultural background, as well as linkage disequilibrium structure and allele frequency. In this study, we conducted a GWAS of MDD susceptibility in a Japanese population, along with a polygenic risk score (PRS) analysis based on the same ancestry. Methods A total of 842 patients diagnosed with MDD according to DSM-IV or DSM-5 criteria were enrolled from Kansai Medical University Hospital and affiliates institutions. Genotyping was performed using three Illumina platforms: HumanOmniExpressExome (n = 123), Asian Screening Array v1.0 (n = 381), and Japanese Screening Array v1.0 (n = 338). Control samples(n=72,839) were obtained from Japanese cohorts: from BioBank Japan, 8,180 atrial fibrillation cases 54,405 general controls, and 10,254 from the Nagahama Study. SNP quality control was performed using PLINK v1.9 applying filters of Hardy-Weinberg equilibrium P < 1 × 10⁻⁷, call rate < 97%, MAF < 1%, and exclusion of sex chromosome variants. Related individuals (PIHAT ≥ 0.5) and ancestry outliers identified via PCA using 1000 Genomes Project references were removed. Phasing and imputation were conducted using SHAPEIT5 and Minimac4, referencing the JPT panel. SNPs with imputation Rsq ≥ 0.8 were retained. GWAS for MDD onset was conducted using GCTA v1.94.1 for three case-control datasets by genotyping platform: (1) 122 cases vs. 8,176 controls, (2) 355 vs. 51,370, and (3) 329 vs. 9,229. Meta-analysis was performed using METAL. PRS analyses were carried out using PRS-CS, in which GWAS results from each dataset as discovery data and the corresponding genotype data as target data. The study protocol was approved by the relevant institutional review board and conducted in accordance with the Declaration of Helsinki for human research. Written informed consent was obtained from all participants. Results The meta-analysis identified genome-wide significant SNPs (P < 5.0 × 10⁻⁸), however, these did not exhibit consistent effect directions across all three datasets. Notably, among the SNPs at suggestive significance thresholds (P < 5.0 × 10⁻⁷), 9 demonstrated concordant effect directions, including regions near RASGRF2 and ME1, previously implicated in neuropsychiatric phenotypes. PRS analysis restricted to the Japanese population is currently in progress. Discussion This study represents the largest GWAS of MDD conducted exclusively in a Japanese population. Although the sample size remains modest, associations were observed for genes such as RASGRF2 and ME1, which overlap with previously reported loci linked to psychiatric conditions. To minimize potential bias introduced by genotyping platform type, a reanalysis using re-genotyped on a unified platform is currently underway. Results from this reanalysis, along with those from the PRS analysis, will be presented at the conference.

Background Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous neurodevelopmental disorder with a strong genetic basis. De novo variants, spontaneously arising and not inherited, play a pivotal role in ASD pathogenesis. Advancements in sequencing technology have expanded our ability to detect these genetic variants. With advancements in sequencing technology, our group embarked on whole genome sequencing (WGS), a method now in the limelight. This report details our initial WGS analysis on a Japanese ASD trio sample. Aims & Objectives Detect de novo variants of various sizes and types. Ascertain pathogenicity of de novo and other variants. Characterize the clinical phenotypes of ASD patients bearing these pathogenic variants. Method DNA samples was obtained from 57 patients with autism spectrum disorder and their parents. This study was approved by the ethics committee of Nagoya University and each participating institute. Written informed consent was procured from all participants. Preliminary screening ensured the absence of pathogenic copy number variants (CNVs) as identified by array comparative hybridization (aCGH). We performed short-read WGS on the MGI T7 platform and detected rare single nucleotide variants (SNVs) or insertion– deletion variants (INDELs) and rare CNVs. This was followed by a trio analysis to identify de novo, inherited homozygous, and hemizygous variants. Results On average, 60 de novo SNVs and INDELs were detected per individual. Of these, 8 de novo variants localized to exonic regions linked to known ASD genes. We revealed a potential novel loss-of-function variant in BSN, a presynaptic gene. Nine exonic homozygous and hemizygous variants appeared as candidates. Within the rare CNVs encompassing coding regions, we identified 4 de novo, 15 homozygous, and 3 hemizygous variants. This includes a de novo duplication of TRIM49 in a patient with ASD and intellectual disability (ID), a homozygous loss of ARHGAP11B, the human-specific gene in a patient with ASD and ID (both parents exhibited a heterozygous loss of this region). Additionally, 10 rare CNVs, inherited either paternally or maternally, were located in genes previously associated with ASD/DD (developmental disorder), encompassing a maternal duplication of RHEB— a component of the mTOR pathway— in a patient diagnosed with ASD, ID, and a brain tumor. A maternal 15q11.2 duplication was also detected in another patient with ASD and ID. Furthermore, while estimating clinical significance was challenging, CNVs encompassing non-coding regions and regulatory elements related to known ASD/DD genes were also identified in several patients. Notably, ASD patients with discernible pathogenic variants often exhibited comorbidities, such as ID, epilepsy, and distinct physical traits. Utilizing WGS enhanced the detection rate of variants that elucidated the underlying pathogenesis of ASD. Discussion & Conclusion Our trio-based WGS strategy facilitated the detection of minute CNVs, overlooked by aCGH. This approach yielded a more precise evaluation of the pathogenic and clinical implications when contrasted with parental genetic information. While our current short-read methodology had its limitations with certain sequences, the advent and adoption of long-read sequencing promises more accurate analyses in forthcoming studies.

Aim:Carbamazepine (CBZ) remains a common antiseizure medication for focal epilepsy but carries the risk of cutaneous adverse drug reactions (cADRs), including Stevens-Johnson syndrome and toxic epidermal necrolysis. The HLA-A*31:01 allele is associated with increased risk of CBZ-induced cADRs, with notably high prevalence (8.4%) in the Japanese population. While genetic screening before CBZ treatment has proven cost-effective in other populations, its economic value in Japan remains unexplored. Methods:We conducted a cost-effectiveness analysis comparing two strategies for newly diagnosed focal epilepsy treatment: (1) screening HLA-A*31:01 before CBZ treatment, with CBZ for negative results and levetiracetam for positive results, and (2) CBZ treatment without screening. Effectiveness was measured in quality-adjusted life years (QALYs) based on utility values scored from 0 (death) to 1 (perfect health). We developed a decision tree model based on a Markov model with monthly cycles and a 20-year follow-up, analyzed from the Japanese healthcare perspective. We utilized clinical trial data and regional cost estimates to conduct base-case and sensitivity analyses. The willingness-to-pay (WTP) threshold was set at 33,784 USD. Results:The incremental cost-effectiveness ratio was 6956 USD/QALY, below the WTP threshold of 33,784 USD, indicating high cost-effectiveness. Probabilistic sensitivity analyses revealed that the probability of the HLA screening strategy being cost-effective was 97.0%, confirming stable cost-effectiveness. Conclusion:HLA-A*31:01 screening before CBZ treatment is cost-effective in the Japanese population. These findings support incorporating genetic screening into Japan's healthcare coverage system to enable more personalized medicine approaches in epilepsy treatment.

Background Bipolar disorder (BD) is a genetically and clinically heterogeneous condition that shares part of its polygenic architecture with schizophrenia (SCZ) and major depressive disorder (MDD). Previous studies have shown that while European BD subtype I (BD1) is more strongly genetically correlated with SCZ, Japanese BD1 is more strongly associated with MDD, suggesting cross-population differences in BD’s genetic architecture. However, genetic correlations alone cannot capture multivariate genetic structures. Genomic structural equation modeling (GSEM), by contrast, allows multivariate modeling of genetic relationships among psychiatric traits and can identify latent factors that underlie observed genetic correlations across disorders. Methods We applied GSEM to genome-wide association study (GWAS) summary statistics for SCZ, BD, and MDD from both East Asian (including Japanese BD from our own cohort) and European populations. Genetic correlations among nine psychiatric traits were estimated using LDSC, with Popcorn used for cross-population comparisons. The best-fitting GSEM model was selected by comparing alternative model structures, and latent factors were interpreted based on trait loadings. Results As previously reported, Japanese BD1 was more strongly genetically correlated with MDD (e.g., MDD_EAS, rg = 0.40) than with SCZ (e.g., SCZ_JPN, rg = 0.29), while European BD1 showed stronger correlation with SCZ than with MDD. Japanese BD2 demonstrated relatively high genetic correlations with both SCZ (rg = 0.50) and MDD (rg = 0.77), indicating a heterogeneous genetic profile. GSEM identified four latent factors: F1 (European SCZ), F2 (Asian SCZ), F3 (BD), and F4 (MDD). European BD1 loaded on F1, Japanese BD1 loaded on F4 along with MDD traits, and Japanese BD2 loaded on F2 with Asian SCZ phenotypes. In contrast, European BD2 loaded only on F3 (BD), indicating a genetically more mood-specific profile. Discussion These findings highlight population-specific differences in the genetic structure of BD. In Japan, psychotic features are less frequently observed in BD1 (30%) than in Western cohorts. Cultural factors such as tolerance of mood symptoms may lead to under-recognition of mania and reclassification of psychotic depression as BD2. Consequently, Japanese BD2 may include individuals who would be diagnosed with BD1 in Western settings. This is consistent with our GSEM results showing Japanese BD2 genetically aligns with European BD1. Such individuals may benefit from antipsychotic treatment, especially if psychotic symptoms are present. Overall, our results emphasize the need for culturally informed diagnostic and treatment strategies for BD.

Mitochondrial dysfunction has been suggested to play a role in depression pathogenesis. This clinical trial (jRCTs042220011) was conducted to evaluate whether depression symptoms could be alleviated by an Extremely Low Frequency, Extremely Low Magnetic Environment (ELF-ELME), which has been found in basic research studies to enhance mitochondrial membrane potential. Participants were exposed to the ELF-ELME via a headmounted magnetic field device (10 mu Tesla, 4 ms, 1 -8 Hz/8 s) worn for 2 h per day for 8 consecutive weeks. Four male patients with treatment -resistant depression were enrolled. Significant reductions from baseline in the average total Montgomery -& Aring;sberg Depression Rating Scale (MADRS) score were observed at 4, 6, and 8 weeks. ELF-ELME appears to ameliorate depressive symptoms in patients with major depressive disorder safely and effectively, suggesting that it could be used as an alternative treatment for depressive patients who do not prefer to take antidepressants and in combination with antidepressant therapy for patients who only partially respond to pharmacotherapy.

Psychiatric disorders are highly inheritable, and most psychiatric disorders exhibit genetic overlap. Recent studies associated the 3q29 recurrent deletion with schizophrenia (SCZ) and autism spectrum disorder (ASD). In this study, we investigated the association of genes in the 3q29 region with SCZ and ASD. TM4SF19 and PAK2 were chosen as candidate genes for this study based on evidence from previous research. We sequenced TM4SF19 and PAK2 in 437 SCZ cases, 187 ASD cases and 524 controls in the Japanese population. Through targeted sequencing, we identified 6 missense variants among the cases (ASD & SCZ), 3 missense variants among controls, and 1 variant common to both cases and controls; however, no loss-of-function variants were identified. Fisher's exact test showed a significant association of variants in TM4SF19 among cases (p=0.0160). These results suggest TM4SF19 variants affect the etiology of SCZ and ASD in the Japanese population. Further research examining 3q29 region genes and their association with SCZ and ASD is thus needed.

Whole genome analysis has identified rare copy number variations (CNV) that are strongly involved in the pathogenesis of psychiatric disorders, and 3q29 deletion has been found to have the largest effect size. The 3q29 deletion mice model (3q29-del mice) has been established as a good pathological model for schizophrenia based on phenotypic analysis; however, circadian rhythm and sleep, which are also closely related to neuropsychiatric disorders, have not been investigated. In this study, our aims were to reevaluate the pathogenesis of 3q29-del by recreating model mice and analyzing their behavior and to identify novel new insights into the temporal activity and temperature fluctuations of the mouse model using a recently developed small implantable accelerometer chip, Nano-tag. We generated 3q29-del mice using genome editing technology and reevaluated common behavioral phenotypes. We next implanted Nano-tag in the abdominal cavity of mice for continuous measurements of long-time activity and body temperature. Our model mice exhibited weight loss similar to that of other mice reported previously. A general behavioral battery test in the model mice revealed phenotypes similar to those observed in mouse models of schizophrenia, including increased rearing frequency. Intraperitoneal implantation of Nano-tag, a miniature acceleration sensor, resulted in hypersensitive and rapid increases in the activity and body temperature of 3q29-del mice upon switching to lights-off condition. Similar to the 3q29-del mice reported previously, these mice are a promising model animals for schizophrenia. Successive quantitative analysis may provide results that could help in treating sleep disorders closely associated with neuropsychiatric disorders.

Aim: Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous neurodevelopmental disorder with a strong genetic basis. Conducting the first comprehensive whole-genome sequencing (WGS) analysis of Japanese ASD trios, this study aimed to elucidate the clinical significance of pathogenic variants and enhance the understanding of ASD pathogenesis. Methods: WGS was performed on 57 Japanese patients with ASD and their parents, investigating variants ranging from single-nucleotide variants to structural variants (SVs), short tandem repeats (STRs), mitochondrial variants, and polygenic risk score (PRS). Results: Potentially pathogenic variants that could explain observed phenotypes were identified in 18 patients (31.6%) overall and in 10 of 23 patients (43.5%) with comorbid intellectual developmental disorder (IDD). De novo variants in PTEN, CHD7, and HNRNPH2 were identified in patients referred for genetic counseling who exhibited previously reported phenotypes, including one patient with ASD who had profound IDD and macrocephaly with PTEN L320S. Analysis of the AlphaFold3 protein structure indicated potential inhibition of intramolecular interactions within PTEN. SV analysis identified deletions in ARHGAP11B and TMLHE. A pathogenic de novo mitochondrial variant was identified in a patient with ASD who had a history of encephalitis and cognitive decline. GO enrichment analysis of genes with nonsense variants and missense variants (Missense badness, PolyPhen-2, and Constraint >1) showed associations with regulation of growth and ATP-dependent chromatin remodeler activity. No reportable results were obtained in the analysis of STR and PRS. Conclusion: Characterizing the comprehensive genetic architecture and phenotypes of ASD is a fundamental step towards unraveling its complex biology.

Recent genetic studies have found common genomic risk variants among psychiatric disorders, strongly suggesting the overlaps in their molecular and cellular mechanism. Our research group identified the variant in ASTN2 as one of the candidate risk factors across these psychiatric disorders by whole-genome copy number variation analysis. However, the alterations in the human neuronal cells resulting from ASTN2 variants identified in patients remain unknown. To address this, we used patient-derived and genome-edited iPS cells with ASTN2 deletion; cells were further differentiated into neuronal cells. A comprehensive gene expression analysis using genome-edited iPS cells with variants on both alleles revealed that the expression level of ZNF558, a gene specifically expressed in human forebrain neural progenitor cells, was greatly reduced in ASTN2-deleted neuronal cells. Furthermore, the expression of the mitophagy-related gene SPATA18, which is repressed by ZNF558, and mitophagy activity were increased in ASTN2-deleted neuronal cells. These phenotypes were also detected in neuronal cells differentiated from patient-derived iPS cells with heterozygous ASTN2 deletion. Our results suggest that ASTN2 deletion is related to the common pathogenic mechanism of psychiatric disorders by regulating mitophagy via ZNF558.

Aim: Bipolar disorder (BD) is a common psychiatric disorder characterized by alterations between manic/hypomanic and depressive states. Rare pathogenic copy number variations (CNVs) that overlap with exons of synaptic genes have been associated with BD. However, no study has comprehensively explored CNVs in synaptic genes associated with BD. Here, we evaluated the relationship between BD and rare CNVs that overlap with synaptic genes, not limited to exons, in the Japanese population. Methods: Using array comparative genome hybridization, we detected CNVs in 1839 patients with BD and 2760 controls. We used the Synaptic Gene Ontology database to identify rare CNVs that overlap with synaptic genes. Using gene-based analysis, we compared their frequencies between the BD and control groups. We also searched for synaptic gene sets related to BD. The significance level was set to a false discovery rate of 10%. Results: The RNF216 gene was significantly associated with BD (odds ratio, 4.51 [95% confidence interval, 1.66-14.89], false discovery rate < 10%). The BD-associated CNV that corresponded with RNF216 also partially overlapped with the minimal critical region of the 7p22.1 microduplication syndrome. The integral component of the postsynaptic membrane (Gene Ontology:0099055) was significantly associated with BD. The CNV overlapping with the intron region of GRM5 in this gene set showed a nominal significant association between cases and controls (P < 0.05). Conclusion: We provide evidence that CNVs in RNF216 and postsynaptic membrane-related genes confer a risk of BD, contributing to a better understanding of the pathogenesis of BD.

Indoleamine 2,3-dioxygenase 2 (IDO2) is an enzyme of the tryptophan-kynurenine pathway that is constitutively expressed in the brain. To provide insight into the physiological role of IDO2 in the brain, behavioral and neurochemical analyses in IDO2 knockout (KO) mice were performed. IDO2 KO mice showed stereotyped behavior, restricted interest and social deficits, traits that are associated with behavioral endophenotypes of autism spectrum disorder (ASD). IDO2 was colocalized immunohistochemically with tyrosine-hydroxylase-positive cells in dopaminergic neurons. In the striatum and amygdala of IDO2 KO mice, decreased dopamine turnover was associated with increased α-synuclein level. Correspondingly, levels of downstream dopamine D1 receptor signaling molecules such as brain-derived neurotrophic factor and c-Fos positive proteins were decreased. Furthermore, decreased abundance of ramified-type microglia resulted in increased dendritic spine density in the striatum of IDO2 KO mice. Both chemogenetic activation of dopaminergic neurons and treatment with methylphenidate, a dopamine reuptake inhibitor, ameliorated the ASD-like behavior of IDO2 KO mice. Sequencing analysis of exon regions in IDO2 from 309 ASD samples identified a rare canonical splice site variant in one ASD case. These results suggest that the IDO2 gene is, at least in part, a factor closely related to the development of psychiatric disorders.

International Journal of Geriatric PsychiatryVolume 38, Issue 1 e5863 LETTER TO THE EDITOR Electroconvulsive therapy as a potential therapeutic option in psychiatric-onset prodromal dementia with Lewy bodies Hiroki Kimura, Hiroki Kimura Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, JapanSearch for more papers by this authorHaruka Yokoyama, Haruka Yokoyama Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, JapanSearch for more papers by this authorYouta Torii, Youta Torii Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, JapanSearch for more papers by this authorHiroshige Fujishiro, Corresponding Author Hiroshige Fujishiro [email protected] orcid.org/0000-0001-9822-5432 Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan Correspondence Hiroshige Fujishiro, Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, Achi466-8550, Japan. Email: [email protected]Search for more papers by this author Hiroki Kimura, Hiroki Kimura Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, JapanSearch for more papers by this authorHaruka Yokoyama, Haruka Yokoyama Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, JapanSearch for more papers by this authorYouta Torii, Youta Torii Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, JapanSearch for more papers by this authorHiroshige Fujishiro, Corresponding Author Hiroshige Fujishiro [email protected] orcid.org/0000-0001-9822-5432 Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan Correspondence Hiroshige Fujishiro, Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, Achi466-8550, Japan. Email: [email protected]Search for more papers by this author First published: 08 December 2022 https://doi.org/10.1002/gps.5863Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. REFERENCES 1 Fukatsu T, Kanemoto K. Electoconvulsive therapy improves psychotic symptoms in patients with dementia with Lewy bodies. 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Recent genetic studies have found common genomic risk variants among schizophrenia (SCZ), autism spectrum disorder (ASD), and bipolar disorder (BP), strongly suggesting the overlaps in their molecular and cellular mechanism. Our research group identified the variant in ASTN2 as one of the candidate risk factors across these psychiatric disorders by whole-genome copy number variation analysis. However, the alterations in the human neuronal cells resulting from ASTN2 variants identified in patients remain unknown. To address this, we used patient-derived and genome-edited iPS cells with ASTN2 deletion; cells were further differentiated into neuronal cells. A comprehensive gene expression analysis revealed that the expression level of ZNF558 , a gene specifically expressed in human forebrain neural progenitor cells, was greatly reduced in ASTN2 -deleted neuronal cells. Furthermore, the expression of the mitophagy-related gene SPATA18 , which is repressed by ZNF558 , and mitophagy activity were increased in ASTN2 -deleted neuronal cells. These phenotypes were detected in both neuronal cells from patient-derived and genome-edited iPS cells with ASTN2 deletion. Our results suggest that ASTN2 deletion is related to the common pathogenic mechanism of SCZ, ASD, and BP by regulating mitophagy via ZNF558 .

Abstract Background Chromosome 16p13.11 duplication is a well‐known genetic risk factor for schizophrenia (SCZ) (odds ratio = 1.84). However, no case reports focusing on patients with SCZ and 16p13.11 duplication have been published. Therefore, here, we report the detailed clinical cases of four patients with SCZ and 16p13.11 duplication who were identified in our previous whole‐genome copy number variant (CNV) study. Case Presentation In the four patients with SCZ and 16p13.11 duplication detected by array comparative genomic hybridization, one patient was found to have treatment‐resistant SCZ and an additional pathogenic rare CNV. Two of the four patients in this study had environmental risk factors that may have been involved in the development of SCZ. Conclusions The results of this case series suggest that a genetic cohort study would be useful for evaluating which genetic and environmental risk factors could better explain the variable expressivity of 16p13.11 duplication. Furthermore, this work could be useful for elucidating the pathophysiology of SCZ.