Search

MicroRNAs (miRNAs) have been investigated in neurodevelopmental and psychiatric disorders including schizophrenia (SZ). Previous studies showed miRNAs dysregulation in postmortem brain tissues and peripheral blood of SZ patients. These suggest that miRNAs may play a role in the pathophysiology of SZ and be a potential biomarker of SZ. Previous studies also showed that miRNAs regulated neurogenesis and that neurogenesis was involved in the pathophysiology of SZ. In addition, a recent study showed that miR-19a and 19b, enriched in neural progenitor cells (NPC) in adult hippocampus, were increased in human NPC derived from induced pluripotent stem cell derived from SZ patients. However, it remains unclear whether the levels of miR-19a and 19b are altered in peripheral blood of SZ patients and how miR-19a and 19b affects neurogenesis. To elucidate them, first we examined the levels of miR-19a and 19b in peripheral blood of SZ patients with quantitative RT-PCR and showed that the level of miR-19b, but not miR-19a, was significantly higher (miR-19a: p = 0.5733, miR-19b: p = 0.0038) in peripheral blood of SZ patients (N = 22) than that of healthy controls (N = 19). Next, we examined the involvement of miR-19b in proliferation and survival of mouse neonatal mice hippocampus-derived NPC with BrdU assay and TUNEL assay. The silencing of miR-19b significantly increased proliferation (N = 5, p = 0.0139), but not survival (N = 5, p = 0.9571), of neonatal mice hippocampus-derived NPC. These results suggest that the level of miR-19b in peripheral blood is a potential biomarker of schizophrenia and that the higher level of miR-19b may increase the vulnerability of SZ via attenuating proliferation of hippocampal NPC.

(1) Background: The COVID-19 pandemic has distressed many populations worldwide, and since its beginning, many institutes have performed cross-sectional studies to assess mental health. We longitudinally examined psychological distress and depressive symptoms among university staff in Japan from 2019 to 2021, before and during the COVID-19 pandemic.; (2) Methods: Participants were teachers and hospital staff working at institutions related to Kobe University, who completed the Brief Job Stress Questionnaire (BJSQ) from 2019 to 2021. This study used the definition recommended by the guideline to identify high-stress. We analyzed the relationship between those who identified as having high-stress before versus during the COVID-19 pandemic using logistic regression analysis (adjusted for age, sex, and occupation).; (3) Results: Results showed that Stress Reaction scores increased slightly in 2020 and significantly in 2021. Time and other factors had a synergistic effect on mental health. The increase in Stress Reaction was significantly associated with females and nurses over the three years. Those with high-stress in 2019 had approximately twenty-fold odds ratios (OR) of having high-stress in 2020 and 2021.; (4) Conclusions: The long-term COVID-19 pandemic may disturb university staff’s mental health. Those who originally experienced high levels of stress were vulnerable to the negative effects of the COVID-19 pandemic.

BACKGROUND Numerous studies suggest that inflammation plays a key role in suicidal behavior. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has received increasing attention in depression research. However, no study has investigated whether MIF has genetic involvement in completed suicide. In this study, we sought to explore the relationship between two functional polymorphisms on the MIF gene promoter (MIF-794CATT5-8 microsatellite and MIF-173G/C single-nucleotide polymorphism [SNP]) and completed suicide by using one of the largest samples of suicide completers ever reported. METHODS The subjects comprised 602 suicide completers and 728 healthy controls. We genotyped MIF-794CATT5-8 microsatellite by polymerase chain reaction-based size discrimination assay and MIF-173G/C SNP by TaqMan® SNP genotyping assay. The allele-, genotype-, or haplotype-based association analyses between the suicide completers and the controls were carried out with the χ2 test, the Cochran-Armitage trend test, or Fisher's exact test. RESULTS Analyses of allele or genotype frequency distributions of the polymorphisms studied here did not reveal any significant differences between the suicide completers and the controls. Haplotype analysis also revealed no association with completed suicide. CONCLUSION To our knowledge, this is the first study that has examined the genetic association between MIF and completed suicide. Our results suggest that the effects of MIF-794CATT5-8 microsatellite and MIF-173G/C SNP on the MIF gene promoter might not contribute to the genetic risk of completed suicide in the Japanese population.

Tadasu Horai,1 Akitoyo Hishimoto,1 Ikuo Otsuka,1 Tatsuhiro So,2 Kentaro Mouri,1 Naofumi Shimmyo,1 Shuken Boku,1 Noriaki Okishio,3 Ichiro Sora1 1Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japan; 2So Mental Clinic, Kobe, Japan; 3Hyogo Mental Health Center, Kobe, Japan Background: Alcohol dependence induces low bone mineral density (BMD), predicting osteoporosis, while low and moderate alcohol consumption may even increase BMD. In recent years, undercarboxylated osteocalcin (ucOC) and tartrate-resistant acid phosphatase-5b (TRACP-5b), bone turnover markers, have gained special interest as useful indicators of low BMD. However, it remains unclear whether other alcohol-related variables (eg, duration of abstinence and continuous drinking) are linked to aberrant BMD. In addition, no previous study has investigated whether ucOC or TRACP-5b is clinically useful to predict low BMD not only in the general population, but also in alcohol-dependent subjects.Patients and methods: We recruited 275 male alcohol-dependent subjects and collected information about their drinking habits, comorbid diseases, smoking history and walking exercise behavior. BMD in each subject was determined by ultrasonography. Serum liver enzymes (AST, ALT, ALP, ChE, γ-GTP and LDH), ucOC and TRACP-5b were measured in all subjects. T-scores were calculated according to BMD for all subjects.Results: The mean T-scores of our subjects were negatively shifted compared to the general population (-0.75±1.36 SD). We divided our subjects into a normal BMD group (n=137) and a low BMD group (n=138) according to their T-scores (T-score ≥-1 SD, normal BMD; T-score

Ikuo Otsuka,1 Yuichiro Watanabe,2 Akitoyo Hishimoto,1 Shuken Boku,1 Kentaro Mouri,1 Kyoichi Shiroiwa,1 Satoshi Okazaki,1 Ayako Nunokawa,2 Osamu Shirakawa,3 Toshiyuki Someya,2 Ichiro Sora1 1Department of Psychiatry, Graduate School of Medicine, Kobe University, Kobe, 2Department of Psychiatry, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, 3Department of Neuropsychiatry, School of Medicine, Kinki University, Osaka, Japan Background: Cadherin13 (CDH13) is a glycosylphosphatidylinositol-anchored cell adhesion molecule that plays a crucial role in morphogenesis and the maintenance of neuronal circuitry. CDH13 has been implicated in the susceptibility to a variety of psychiatric diseases. A recent genome-wide association study using Danish samples showed, for the first time, the involvement of a single nucleotide polymorphism (SNP) of CDH13 (intronic SNP rs8057927) in schizophrenia. Here, we investigated the association between other SNPs of CDH13 and schizophrenia and tried to replicate the association for the SNP of rs8057927, in the Japanese population.Methods: Using TaqMan® SNP genotyping assays, five tag SNPs (rs12925602, rs7193788, rs736719, rs6565051, and rs7204454) in the promoter region of CDH13 were examined for their association with schizophrenia in two independent samples. The first sample comprised 665 patients and 760 controls, and the second sample comprised 677 patients and 667 controls. One tag SNP for rs8057927 was also examined for the association with schizophrenia in the first sample set.Results: A GACAG haplotype of the five SNPs in the promoter region of CDH13 was significantly associated with schizophrenia in the first sample set (P=0.016 and corrected P=0.098). A combined analysis of the GACAG haplotype with the second sample set enhanced the significance (P=0.0026 and corrected P=0.021). We found no association between rs8057927 and schizophrenia in the first sample set.Conclusion: Our results suggest that CDH13 may contribute to the genetic risk of schizophrenia. Further replication on the association of CDH13 with schizophrenia and functional studies are required to confirm the current findings. Keywords: CDH13, promoter region, haplotype, SNP

Background Numerous studies suggest that inflammation plays a key role in suicidal behavior. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has received increasing attention in depression research. However, no study has investigated whether MIF has genetic involvement in completed suicide. In this study, we sought to explore the relationship between two functional polymorphisms on the MIF gene promoter (MIF-794CATT5–8 microsatellite and MIF-173G/C single-nucleotide polymorphism [SNP]) and completed suicide by using one of the largest samples of suicide completers ever reported. Methods The subjects comprised 602 suicide completers and 728 healthy controls. We genotyped MIF-794CATT5–8 microsatellite by polymerase chain reaction–based size discrimination assay and MIF-173G/C SNP by TaqMan® SNP genotyping assay. The allele-, genotype-, or haplotype-based association analyses between the suicide completers and the controls were carried out with the χ2 test, the Cochran–Armitage trend test, or Fisher’s exact test. Results Analyses of allele or genotype frequency distributions of the polymorphisms studied here did not reveal any significant differences between the suicide completers and the controls. Haplotype analysis also revealed no association with completed suicide. Conclusion To our knowledge, this is the first study that has examined the genetic association between MIF and completed suicide. Our results suggest that the effects of MIF-794CATT5–8 microsatellite and MIF-173G/C SNP on the MIF gene promoter might not contribute to the genetic risk of completed suicide in the Japanese population.

Short telomere length (TL) occurs in individuals under psychological stress, and with various psychiatric diseases. Recent studies have also reported mitochondrial DNA copy number (mtDNAcn) alterations under several neuropsychiatric conditions. However, no study has examined whether aberrant TL or mtDNAcn occur in completed suicide, one of the most serious outcomes of mental illnesses. TL and mtDNAcn in post-mortem samples from 528 suicide completers without severe physical illness (508 peripheral bloods; 20 brains) and 560 samples from control subjects (peripheral bloods from 535 healthy individuals; 25 post-mortem brains) were analysed by quantitative polymerase chain reaction. Suicide completers had significantly shorter TL and higher mtDNAcn of peripheral bloods with sex/age-dependent differences (shorter TL was more remarkably in female/young suicides; higher mtDNAcn more so in male/elderly suicides). The normal age-related decline of TL and mtDNAcn were significantly altered in suicide completers. Furthermore, shorter TL and lower mtDNAcn of post-mortem prefrontal cortex were seen in suicide completers compared to controls. This study shows the first association of aberrant telomeres and mtDNA content with suicide completion. Our results indicate that further research on telomere shortening and mitochondrial dysfunction may help elucidate the molecular underpinnings of suicide-related pathophysiology.

The accelerated aging hypothesis of schizophrenia (SCZ) has been proposed. DNA methylation profiles were developed for determining “epigenetic age.” Here, we assessed intrinsic and extrinsic epigenetic age acceleration (IEAA and EEAA, respectively) in SCZ. We examined two independent cohorts of Japanese ancestry. The first cohort consisted of 80 patients with SCZ under long-term or repeated hospitalization and 40 controls, with the economical DNA pooling technique. The second cohort consisted of 24 medication-free patients with SCZ and 23 controls. Blood of SCZ subjects exhibited decreased EEAA in the first cohort (p = 0.0162), but not in the second cohort. IEAA did not differ in either cohort. We performed replication analyses using publicly available datasets from European ancestry (three blood and one brain datasets). One blood dataset showed increased EEAA in SCZ (p = 0.0228). Overall, our results provide evidence for decreased EEAA in SCZ associated with hospitalization in the Japanese population.

Background Cell adhesion molecules (CAMs) play pivotal role in the development of the central nervous system (CNS) and have also been reported to play role in the pathophysiology of schizophrenia. Missense mutations in the CAMs genes might alter the binding of their ligands, increasing the vulnerability to develop schizophrenia. Methods We selected 15 missense mutations in the CAMs genes of the CNS reported in the Kyoto Encyclopedia of Genes and Genomes (KEGG) and examined the association between these mutations and schizophrenia in 278 patients and 284 control subjects (first batch). We also genotyped the positive single nucleotide polymorphisms (SNPs) in 567 patients and 710 control subjects (second batch) and in 635 patients and 639 control subjects (replication samples). Results Genotypic and allelic distributions of rs2298033 in the ITGA8 gene between the schizophrenia and control groups were significantly different in the first batch (p = 0.005 and 0.007, respectively). Gender-based analysis revealed that the allelic and genotypic distributions of rs2298033 in the ITGA8 were significantly different between the schizophrenia and control groups among females in both batches (p = 0.010, 0.011 and 0.0086, 0.010, respectively) but not among males. Combine analysis of rs2298033 with the replication samples revealed a more significant differences (p = 0.0032; 0.0035 in the overall subjects and p = 0.0024; 0.0025 in the female subjects, respectively). The significant differences for rs2802808 of the NFASC gene were only observed in the female subgroup of the first batch. Conclusion These results suggest that the ITGA8 gene might have gender-specific roles in the development of schizophrenia. Further replication and functional studies are required to confirm these findings.

In order for hospitals to work efficiently in a pandemic, it is important to know how a pandemic affects the hospital staff. The aim of the present study was to investigate the psychological impact of the pandemic (H1N1) 2009 on hospital workers and how it was affected by the characteristics of the hospital, gender, age, job and work environment.In late June 2009, soon after the pandemic had ended in Kobe city, Japan, a questionnaire was distributed consisting of questions on sociodemographic characteristics, 19 stress-related questions and the Impact of Event Scale (IES) to all 3635 employees at three core general hospitals in Kobe. Exploratory factor analysis was applied to the 19 stress-related questions, and this produced four factors for evaluation (anxiety about infection, exhaustion, workload, and feeling of being protected). Multiple regression models were used to evaluate the association of personal characteristics with each score of the four factors and the IES.Valid answers were received from 1625 employees. Workers at a hospital with intense liaison psychiatric services felt less psychological impact. Workers at a hospital that provided staff with information about the pandemic less frequently, felt unprotected. Workers in work environments that had a high risk of infection felt more anxious and more exhausted. The total IES score was higher in workers in high-risk work environments.It is important for hospitals to protect hospital workers during a pandemic and to rapidly share information about the pandemic. Liaison psychiatric services can help to reduce the impact of the pandemic on hospital workers.

Genetic factors for panic disorder have been consistently observed in family and twin studies. Regulators of G-protein signaling (RGS) is a family of proteins that negatively regulate the intracellular signaling of G protein-coupled receptors such as dopamine and serotonin receptors. RGS2, one of the RGS families, has been suggested to plays a role in anxiety and/or aggressive behavior. Polymorphisms in the RGS2 gene were recently associated with panic disorder, trait anxiety, suicidal behavior, and generalized anxiety disorder. From these findings, we tried to replicate an association between panic disorder and genetic variations of the RGS2 using a case-control study of 186 patients with panic disorder and 380 controls in Japanese. We genotyped five common single nucleotide polymorphisms (SNPs) by the PCR-RFLP method and the TaqMan Assays. Neither genotype distribution nor allele frequency for five SNPs was significant different between the panic disorder and control groups. We found a relative tight LD block in the 5'- flanking region of RGS2 gene. One of the common haplotypes, AC of rs2746071 and rs2746072, has shown a nominally significant association with panic disorder (p=0.027). This significance, however, did not remain after correction for multiple testing. These findings suggest that RGS2 may not be genetically involved in the biological susceptibility to panic disorder in Japanese.

Epidemiological studies have shown that excessive alcohol consumption is a potent risk factor to develop suicidal behavior. Genetic factors for suicidal behavior have been observed in family, twin, and adoption studies. Because alcohol dehydrogenase (ADH1B) His47Arg and mitochondrial aldehyde dehydrogenase (ALDH2) Glu487Lys single nucleotide polymorphisms (SNPs), which affect alcohol metabolism, have been reported to exert significant impacts on alcohol consumption and on the risk for alcoholism in East Asia populations, we explored associations of the two functional SNPs with suicide using a case-control study of 283 completed suicides and 319 control subjects in the Japanese population. We found that the inactive ALDH2 allele (487Lys) was significantly less frequent in the completed suicides (19.3%) than in the controls (29.3%), especially in males, whereas this was not the case in females. The males bearing alcoholism-susceptible homozygotes at both loci (inactive ADH1B Arg/Arg and active ALDH2 Glu/Glu genotypes) have a 10 times greater risk for suicide compared with the males bearing alcoholism-protective homozygotes at both loci. Our data show the genetic impact of the two polymorphisms on suicidal behavior in the Japanese population, especially in males. Because we did not verify the daily alcohol consumption, the association of these SNPs with suicide might be due to alcoholism itself. Further studies using case-control subjects, which verifies the details of current and past alcohol consumption and diagnosis for alcoholism, are required to confirm these findings.

Excessive alcohol consumption plays a crucial role in the pathogenesis of suicide. Because certain functional alleles of alcohol dehydrogenase (ADH1B) and mitochondrial aldehyde dehydrogenase (ALDH2) genes affect alcohol consumption, we explored associations of the ADH1B and ALDH2 genetic variants with suicide in 317 Japanese males. We found the active ALDH2 allele was significantly more frequent in the completed suicides. Individuals bearing alcoholism-susceptible homozygotes at both loci have 6 times greater risk for suicide. Our data show the genetic impact of the two polymorphisms on suicidal behaviour and presence of the active ALDH2 allele may increase the risk for suicide.