Effects of Metabotropic Glutamate Receptor 3 Genotype on Phonetic Mismatch Negativity

BACKGROUND: The genetic and molecular basis of glutamatergic dysfunction is one key to understand schizophrenia, with the identification of an intermediate phenotype being an essential step. Mismatch negativity (MMN) or its magnetic counterpart, magnetic mismatch field (MMF) is an index of preattentive change detection processes in the auditory cortex and is generated through glutamatergic neurotransmission. We have previously shown that MMN/MMF in response to phoneme change is markedly reduced in schizophrenia. Variations in metabotropic glutamate receptor (GRM3) may be associated with schizophrenia, and has been shown to affect cortical function. Here we investigated the effect of GRM3 genotypes on phonetic MMF in healthy men. METHODS: MMF in response to phoneme change was recorded using magnetoencephalography in 41 right-handed healthy Japanese men. Based on previous genetic association studies in schizophrenia, 4 candidate SNPs (rs6465084, rs2299225, rs1468412, rs274622) were genotyped. RESULTS: GRM3 rs274622 genotype variations significantly predicted MMF strengths (p = 0.009), with C carriers exhibiting significantly larger MMF strengths in both hemispheres compared to the TT subjects. CONCLUSIONS: These results suggest that variations in GRM3 genotype modulate the auditory cortical response to phoneme change in humans. MMN/MMF, particularly those in response to speech sounds, may be a promising and sensitive intermediate phenotype for clarifying glutamatergic dysfunction in schizophrenia

Association between Catechol-O-Methyltrasferase Val108/158Met Genotype and Prefrontal Hemodynamic Response in Schizophrenia

BACKGROUND:"Imaging genetics" studies have shown that brain function by neuroimaging is a sensitive intermediate phenotype that bridges the gap between genes and psychiatric conditions. Although the evidence of association between functional val108/158met polymorphism of the catechol-O-methyltransferase gene (COMT) and increasing risk for developing schizophrenia from genetic association studies remains to be elucidated, one of the most topical findings from imaging genetics studies is the association between COMT genotype and prefrontal function in schizophrenia. The next important step in the translational approach is to establish a useful neuroimaging tool in clinical settings that is sensitive to COMT variation, so that the clinician could use the index to predict clinical response such as improvement in cognitive dysfunction by medication. Here, we investigated spatiotemporal characteristics of the association between prefrontal hemodynamic activation and the COMT genotype using a noninvasive neuroimaging technique, near-infrared spectroscopy (NIRS). METHODOLOGY/PRINCIPAL FINDINGS:Study participants included 45 patients with schizophrenia and 60 healthy controls matched for age and gender. Signals that are assumed to reflect regional cerebral blood volume were monitored over prefrontal regions from 52-channel NIRS and compared between two COMT genotype subgroups (Met carriers and Val/Val individuals) matched for age, gender, premorbid IQ, and task performance. The [oxy-Hb] increase in the Met carriers during the verbal fluency task was significantly greater than that in the Val/Val individuals in the frontopolar prefrontal cortex of patients with schizophrenia, although neither medication nor clinical symptoms differed significantly between the two subgroups. These differences were not found to be significant in healthy controls. CONCLUSIONS/SIGNIFICANCE:These data suggest that the prefrontal NIRS signals can noninvasively detect the impact of COMT variation in patients with schizophrenia. NIRS may be a promising candidate translational approach in psychiatric neuroimaging

CNVs in Three Psychiatric Disorders

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD

No association of DRD2, DRD3, and tyrosine hydroxylase gene polymorphisms with personality traits in the Japanese population

Abstract Background Dopamine D2 receptor (DRD2) and dopamine D3 receptor (DRD3) genes could be candidates for personality-related genes considering their pharmacological profiles or structures. However, a limited number of studies have investigated the association between these genes and personality traits. In the present study, we investigated the DRD2, DRD3, and tyrosine hydroxylase (TH) genes in relation to personality traits in the Japanese population. Epistasis (gene-gene interaction) among the genes was extensively analyzed, in addition to the analysis based on each gene. Methods The -241A/G, -141C Ins/Del, and Ser311Cys polymorphisms in the DRD2 gene, the Ser9Gly polymorphism of the DRD3 gene, and the Val81Met and PstI site polymorphisms in the TH gene were genotyped in 257 healthy Japanese subjects. Personality traits were evaluated by using the Revised NEO Personality Inventory (NEO PI-R) and the State-Trait Anxiety Inventory (STAI). The associations between gene polymorphisms and the scores for NEO PI-R or Trait Anxiety of STAI were statistically analyzed by one-way analysis of covariance (ANCOVA) adjusting sex and age. Epistasis was assessed using two-way ANCOVA between the polymorphisms of independent two genes. Results In the analysis based on each gene, trends for association were observed between State Anxiety and the DRD2 -141C Ins/Del polymorphism (p = 0.031, uncorrected), and between Trait Anxiety and the DRD2 Ser311Cys or TH PstI site polymorphism (p = 0.048 and 0.041, respectively, uncorrected). In epistatic analysis, a trend for interaction was observed on the scores for Neuroticism and Trait Anxiety between the DRD2 -141C Ins/Del and TH Val81Met polymorphisms (p = 0.015 and 0.010, respectively, uncorrected). However, these differences were insignificant after Bonferroni correction. Conclusion The present study did not provide evidence for the association between these dopamine-related genes and personality traits in the Japanese population.</p

A case of methamphetamine use disorder presenting a condition of ultra-rapid cycler bipolar disorder

Methamphetamine, a potent psychostimulant, may cause a condition of mood disorder among users. However, arguments concerning methamphetamine-induced mood disorder remain insufficient. This case study describes a male with methamphetamine-induced bipolar disorder not accompanied by psychotic symptoms, who twice in an 11-year treatment period, manifested an ultra-rapid cycler condition alternating between manic and depressive mood states with 3- to 7-day durations for each. The conditions ensued after a bout of high-dose methamphetamine use and shifted to a moderately depressive condition within 1 month after the use under a treatment regimen of aripiprazole and mood stabilizers. The cycler condition may be characteristic of a type of the bipolar disorder and a sign usable for characterization. Further efforts are needed to seek distinctive features and to improve diagnostic assessment of methamphetamine-induced mood disorders

Irregular bedtime and nocturnal cellular phone usage as risk factors for being involved in bullying: a cross-sectional survey of Japanese adolescents.

PURPOSE: A number of studies have tried to identify risk factors for being involved in bullying in order to help developing preventive measures; however, to our knowledge, no study has investigated the effect of nocturnal lifestyle behavior such as sleep pattern or cellular phone usage. In the present study, we aimed to investigate the relationship between school bullying and sleep pattern or nocturnal cellular phone usage in adolescents. The effect of school size on school bullying was also examined. METHODS: Data from the cross-sectional survey of psychopathologies conducted for 19,436 Japanese students from 45 public junior high schools (7(th)-9(th) grade) and 28 senior high schools (10(th)-12(th) grade) were analyzed. RESULTS: Bullying status was significantly associated with irregular bedtime (OR = 1.23 and 1.41 for pure bullies and bully-victims, respectively) and e-mail exchange or calling after lights-out (OR = 1.53 and 1.31 for pure bullies and bully-victims, respectively) after controlling domestic violence and substance usage. In addition, school size was significantly associated with the increased risk of bullying in junior high school students (OR = 1.13 for bully-victims). CONCLUSIONS: The present results suggested that sleep pattern and nocturnal cellular phone usage might be risk factors for being involved in school bullying in adolescents. Although further accumulation of data is needed, progressive trend towards nocturnal lifestyle and increasing usage of cellular phone might impair the well-being of adolescents. School-based interventions for lifestyle including sleep pattern and cellular phone usage may be encouraged to reduce school bullying