Kazuhisa Kohda

Association between the neurofibromatosis-1 (NF1) locus and autism in the Japanese population

Autistic patients have a 100 to 190‐fold increased risk of neurofibromatosis compared to the general population. This suggests that the two diseases may share a common etiological background. Recently, a new allele (or the six‐repeat allele) of the (AAAT)n repeat polymorphism in an Alu sequence in the neurofibromatosis‐1 (NF1) gene was observed exclusively in severe autistic patients, not in controls, in Caucasians of French ancestry. This suggests a role of the NF1 gene in the development of autism. We investigated three microsatellite polymorphisms within the intron‐27b and intron‐38 of the NF1 region, including the (AAAT)n and two (CA)n repeat polymorphisms, in Japanese subjects with autism (nu2009=u200974) and controls (nu2009=u2009122). The six‐repeat allele of the (AAAT)n polymorphism was not found either in patients or controls, possibly indicating an ethnic difference in the polymorphism. However, significant differences were observed in the allele distributions of the (AAAT)n and a (CA)n, which were located at intron‐27b, between patients and controls, although an association was not significant between autism and another polymorphism at intron‐38. This may suggest an involvement of the NF1 locus in susceptibility to autism, although further investigations are recommended.

Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with schizophrenia in the Japanese population.

Schizophrenia and bipolar disorder share common genetic background. Several loci such as 18p11, 13q32, and 22q11–13 were commonly linked with these diseases. Since mitochondrial dysfunction has been suggested in both of these disorders, NDUFV2 at 18p11, encoding a subunit of the complex I, NADH ubiquinone oxidoreductase, is a candidate gene for these diseases. We previously reported that single nucleotide polymorphisms (SNPs) in the upstream region of NDUFV2 were associated with bipolar disorder in Japanese. The association of haplotype consisting of two SNPs, −3542Gu2009>u2009A and −602Gu2009>u2009A, with bipolar disorder was also seen both in Japanese and the National Institute of Mental Health Pedigrees trios. In this study, 2 polymorphisms, −3542Gu2009>u2009A and −602Gu2009>u2009A, were investigated in 229 schizophrenic patients as compared with controls. Individual genotypes were not associated with schizophrenia. However, the haplotype consisting of these two SNPs were significantly associated with schizophrenia. These results suggested that inter‐individual variation of the genomic sequence of the promoter region of NDUFV2 might be a genetic risk factor common to bipolar disorder and schizophrenia.

Association of the XBP1-116C/G polymorphism with schizophrenia in the Japanese population.

Abstractu2003 Schizophrenia and bipolar disorder share some clinical features and linkage studies have shown that several loci are common. Recently, the authors found that the −116C→G substitution in the promotor region of XBP1, a pivotal gene in endoplasmic reticulum (ER) stress response, causes the impairment of ER stress response, and that the −116C/C genotype is a protective factor; in other words the presence of the G allele increases the risk for bipolar disorder. The gene is located on 22q12.1, which is also linked with schizophrenia. The polymorphisms were investigated in 234 schizophrenic patients as compared with controls. Significant difference of genotype distribution was observed, which suggested that the −116C/C genotype is a protective factor for both of the major mental disorders.

Heteromer formation of δ2 glutamate receptors with AMPA or kainate receptors

Abstract The δ2 glutamate receptor (GluRδ2) is predominantly expressed in the postsynaptic densities of parallel fiber-Purkinje cell synapses and plays a crucial role in cerebellar function. However, the mechanisms by which GluRδ2 participates in cerebellar functions are largely unknown because GluRδ2 does not bind glutamate analogs. We investigated the possibility that GluRδ2 may be involved in channel formation together with other glutamate receptor families. We transiently expressed lurcher mutant AMPA receptor GluR1Lc and kainate receptor GluR6Lc in HEK293 cells. Cells expressing these constitutively active channels displayed a rectifying current–voltage (I–V) relationship. However, when cells were co-transfected with GluRδ2Lc, which had the arginine residue in the channel pore region, cells displayed a linear I–V relationship, a result that indicates GluRδ2Lc formed functional heteromeric channels with GluR1Lc or GluR6Lc. Assembly of GluRδ2 with GluR1 or GluR6 was further confirmed by co-immunoprecipitation assays in HEK293 cells. In addition, GluRδ2 receptors were partially co-immunoprecipitated from cerebellar synaptosomal fractions by antibodies against GluR2 or KA2. In contrast to lurcher channels, expression of wild-type GluRδ2 significantly reduced the glutamate-induced current of the wild-type GluR1 receptors without affecting channel properties, such as current kinetics, dose–response relationship, and single-channel conductance. Thus, the heteromeric channel created by the association of wild-type GluR1 and GluRδ2 may not be gated by glutamate and does not participate in glutamate-induced currents. These results suggest that GluRδ2 and AMPA or kainate receptors can assemble to form heteromeric receptors in vitro and could modify glutamate signaling in vivo. These findings may help explain the role of GluRδ2.

Serotonin transporter-linked promoter region polymorphism and personality traits in a Japanese population

Serotonin transporter gene may play a critical role in a regulation of mood and other aspects of mental status. A large number of association studies have investigated a correlation between the polymorphism in the serotonin transporter-linked promoter region (5-HTTLPR) and anxiety-related personality traits. The results, however, have been inconsistent. Heterogeneity of subjects regarding gender, occupation, social-class and other environmental factors, in addition to effects of other genes, might have confounded the results. Here, we studied an association between the 5-HTTLPR polymorphism and personality traits in primarily female (78%) healthy subjects (n=244), who had homogeneous backgrounds regarding ethnicity (Japanese) and occupation. Personality traits of the subjects were assessed with the revised NEO Personality Inventory. No significant association was observed between the polymorphism and neuroticism or other personality traits, in all subjects, all females (n=190) or female nurses (n=159). Thus, our findings provided no evidence for an association between the 5-HTTLPR polymorphism and anxiety-related or other personality traits.

Maternal separation stress drastically decreases expression of transthyretin in the brains of adult rat offspring

Adversity in early life has been recognized as a risk factor for psychiatric disorders. In experimental animals, maternal separation (MS) during the neonatal period has been shown to be critical for susceptibility to stress in adult offspring. In this study, we used DNA microarray analysis of rat hippocampal samples to investigate differential gene expression caused by 8-hour MS (MS-8h) every other day during the neonatal period. We found 15 up-regulated and 9 down-regulated genes. We added samples from a daily 15-minute MS (MS-15m) group and performed quantitative real-time PCR to validate the results. Expression of transthyretin (TTR), which is specifically expressed in the choroid plexus (CP), was drastically reduced in the MS-8h group. Two other CP-enriched genes, angiotensin I converting enzyme I and insulin-like growth factor II (IGF-II), were also significantly down-regulated in the MS-8h rats, while significant reduction of IGF-II expression was also found in the MS-15m group. These MS-induced differential gene expressions could be involved in the molecular mechanisms of stress susceptibility. Our findings indicate that the CP, in addition to the neuronal and glial system, might play an important role in determining stress susceptibility.

Mitochondrial DNA sequence analysis of patients with ‘atypical psychosis’

Abstractu2002 Although classical psychopathological studies have shown the presence of an independent diagnostic category, ‘atypical psychosis’, most psychotic patients are currently classified into two major diagnostic categories, schizophrenia and bipolar disorder, by the Diagnostic and Statistical Manual of Mental Disorders (4th edn; DSM‐IV) criteria. ‘Atypical psychosis’ is characterized by acute confusion without systematic delusion, emotional instability, and psychomotor excitement or stupor. Such clinical features resemble those seen in organic mental syndrome, and differential diagnosis is often difficult. Because patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes (MELAS) sometimes show organic mental disorder, ‘atypical psychosis’ may be caused by mutations of mitochondrial DNA (mtDNA) in some patients. In the present study whole mtDNA was sequenced for seven patients with various psychotic disorders, who could be categorized as ‘atypical psychosis’. None of them had known mtDNA mutations pathogenic for mitochondrial encephalopathy. Two of seven patients belonged to a subhaplogroup F1b1a with low frequency. These results did not support the hypothesis that clinical presentation of some patients with ‘atypical psychosis’ is a reflection of subclinical mitochondrial encephalopathy. However, the subhaplogroup F1b1a may be a good target for association study of ‘atypical psychosis’.

Mitochondrial DNA polymorphisms and extraversion

Mitochondria is the major site of energy production in cells, therefore, mitochondrial abnormality may affect functions of organs including the brain, which constantly requires high levels of energy consumption. Previous studies have suggested a role of mitochondria and their DNA polymorphisms in neuro‐psychiatric disorders, including Alzheimers disease, Parkinsons disease, schizophrenia and bipolar mood disorder. Thus, we hypothesized that mitochondrial DNA polymorphisms might be related with the development of personality. The present study investigated a role of two mitochondrial DNA polymorphisms, the C5178A and A10398G, in personality traits evaluated using the NEO PI‐R scores in 238 healthy Japanese volunteers. Subjects with the 5178A genotype showed significantly higher extraversion score than those with the 5178C genotype (Pu2009=u20090.027), while no significant association was observed between the C5178A polymorphism and other scores. No significant association was found between the A10398G polymorphism and any scores. Regarding the 5178–10398 haplotype, the score of extraversion, not other scores, was significantly associated with the A–G haplotype (Pu2009=u20090.042). Although further studies are recommended for the confirmation, the result may suggest a role of the mitochondrial DNA polymorphism in the personality trait.

Serotonin 2A receptor gene polymorphism and personality traits: no evidence for significant association.

A number of studies have observed associations between the serotonin 2A (5-HT2A) receptor and mental disorders. Here, we investigated correlations between polymorphisms (−1438G/A and 102T/C) of the 5-HT2A gene and personality traits in healthy Japanese volunteers (n=239). The personality traits were evaluated using the Revised NEO Personality Inventory (NEO PI-R). The −1438G/A and 102T/C were in complete linkage disequilibrium. There was a tendency for associations between the genotype and the scores for Agreeableness, Conscientiousness and Neuroticism of the NEO PI-R (P=0.028, 0.039 and 0.062, respectively; analysis of variance, uncorrected for multiple testing). Subjects with the A/A of −1438G/A (or T/T of 102T/C) appeared to be lower in Neuroticism and higher in Conscientiousness than the rest of the subjects. However, the results were statistically non-significant after Bonferronis correction for multiple testing of the five scales of the NEO PI-R. Thus, the present study provided no evidence for statistically significant associations between the 5-HT2A polymorphisms and the personality traits.

Human leukocyte antigen-A specificities and its relation with season of birth in Japanese patients with schizophrenia

Several studies, including one from Japan, have observed an increase of Human Leukocyte Antigen (HLA)-A24 and A26 in schizophrenia, although others failed to observe the increase. No use of systematic diagnostic criteria and a not-adequately reliable typing technique might have affected the results in the previous studies. We investigated HLA-A specificities in Japanese patients with schizophrenia (DSM-IV), recruited from the same area as in the early Japanese study. A DNA-based technique (polymerase chain reaction-microtiter plate hybridization) was employed. No significant difference was observed in frequencies of any HLA-A specificities between patients and controls, including A24 and A26. No significant association was found between the HLA-A and birth-season in patients. Thus, no evidence was obtained for an association between HLA-A and schizophrenia from the Japanese population.