Possible association between the pituitary adenylate cyclase-activating polypeptide (PACAP) gene and major depressive disorder.

Pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1: adenylate cyclase-activating polypeptide 1) is a neuropeptide with neurotransmission modulating activity. The associations of the PACAP gene with schizophrenia and hippocampal volume have been reported. We recently reported depression-like behavior in the forced swimming test in PACAP deficient mice. Here we examined a possible association between the PACAP gene and major depressive disorder (MDD) in 637 patients and 967 controls and found that a genetic variant in the gene was associated with MDD. The present results suggest that PACAP signaling might contribute to the pathogenesis of MDD.

A genetic variation in the dysbindin gene (DTNBP1) is associated with memory performance in healthy controls.

Schizophrenia is a common psychiatric disorder characterized by disturbances of cognition, emotion and social functioning. There are few studies investigating a possible genetic basis for the underlying mechanism of cognitive dysfunctions. A genetic variation in the dysbindin gene (DTNBP1: dystrobrevin binding protein 1), a susceptibility gene for schizophrenia, has been reported to be associated with general cognitive ability and cognitive decline in patients with schizophrenia. Although profound disturbances of memory performance are observed in schizophrenia, only one study has reported a relationship between this gene and spatial working memory in a Caucasian population. We examined a possible association between a protective haplotype of DTNBP1 for developing schizophrenia and memory performance measured by the Wechsler Memory Scale-Revised (WMS-R) and the Wechsler Adult Intelligence Scale-Revised (WAIS-R) in 165 healthy volunteers and 70 patients with schizophrenia in a Japanese population. Healthy controls that carry the protective haplotype showed higher performance in several memory domains measured by the WMS-R than those who did not. Genotype effect on memory performance was not observed in patients with schizophrenia. This haplotype did not affect IQ and its sub-scores as measured by the Wechsler Adult Intelligence Scale-Revised in both groups. These data suggest that DTNBP1 may have impact on parts of memory functions.

Association analysis between schizophrenia and the AP-3 complex genes.

A susceptibility gene for schizophrenia, dysbindin, is a component of BLOC-1, which interacts with the adaptor protein (AP)-3 complex. As a direct interaction between dysbindin and AP-3 complex was reported, we examined a possible association between 16 SNPs in the AP3 complex genes and schizophrenia using 432 cases and 656 controls. Nominal association between rs6688 in the AP3M1 gene and schizophrenia (chi(2)=6.33, P=0.012, odds ratio=0.80) was no longer positive after correction for multiple testing (corrected P=0.192). The present results suggest that AP3 complex genes might not play a major role in the pathogenesis of schizophrenia in this population.

Tumor necrosis factor receptor-associated protein 1 regulates cell adhesion and synaptic morphology via modulation of N-cadherin expression.

An increase in serum tumor necrosis factor-alpha (TNF-alpha) levels is closely related to the pathogenesis of major depression. However, the underlying molecular mechanism between this increase and impairment of brain function remains elusive. To better understand TNF-alpha/TNF receptor 1 signaling in the brain, we analyzed the brain distribution and function of tumor necrosis factor receptor-associated protein 1 (TRAP1). Here we show that TRAP1 is broadly expressed in neurons in the mouse brain, including regions that are implicated in the pathogenesis of major depression. We demonstrate that small interfering RNA-mediated knockdown of TRAP1 in a neuronal cell line decreases tyrosine phosphorylation of STAT3, followed by a reduction of the transcription factor E2F1, resulting in a down-regulation of N-cadherin, and affects the adhesive properties of the cells. In addition, in cultured hippocampal neurons, reduced expression of N-cadherin by TRAP1 knockdown influences the morphology of dendritic spines. We also report a significant association between several single nucleotide polymorphisms in the TRAP1 gene and major depression. Our findings indicate that TRAP1 mediates TNF-alpha/TNF receptor 1 signaling to modulate N-cadherin expression and to regulate cell adhesion and synaptic morphology, which may contribute to the pathogenesis of major depression.

Progressive supranuclear palsy combined with Alzheimer's disease: a clinicopathological study of two autopsy cases.

We present here the clinicopathological characteristics of two autopsy-confirmed cases comorbid of progressive supranuclear palsy (PSP) and Alzheimer's disease (AD). Histopathologically, the amount and distribution of neurofibrillary tangles (NFTs) in the basal ganglia and brainstem fulfilled the pathological criteria of PSP proposed by the National Institute of Neurological Disorders and Stroke--The Society for PSP (NINDS-SPSP). The Braak stages of senile plaques and NFTs were stage C and stage V in Case 1, and stage C and stage IV in Case 2. These neuropathological findings confirmed that the two patients had combined PSP with AD. Our patients presented clinically with executive dysfunction prior to memory disturbance as an early symptom. Not only neurological symptoms such as gait disturbance, supranuclear ophthalmoplegia and pseudobulbar palsy, but emotional and personality changes and delirium were prominent. Therefore, symptoms of subcortical dementia of PSP were more predominant than AD-related symptoms in the present two patients. Comorbid PSP and AD further complicates the clinical picture and makes clinical diagnosis even more difficult.

Genetic variations of human neuropsin gene and psychiatric disorders: polymorphism screening and possible association with bipolar disorder and cognitive functions.

Human neuropsin (NP) (hNP) has been implicated in the progressive change of cognitive abilities during primate evolution. The hNP gene maps to chromosome 19q13, a region reportedly linked to schizophrenia and bipolar disorder. Therefore, hNP is a functional and positional candidate gene for association with schizophrenia, mood disorders, and cognitive ability. Polymorphism screening was performed for the entire hNP gene. The core promoter region was determined and whether or not transcriptional activity alters in an allele-dependent manner was examined by using the dual-luciferase system. Allelic and genotypic distributions of five single-nucleotide polymorphisms (SNPs) were compared between patients with schizophrenia (n=439), major depression (n=409), bipolar disorder (n=207), and controls (n=727). A possible association of the hNP genotype with memory index (assessed with Wechsler Memory Scale, revised, WMS-R) and intelligence quotient (IQ assessed with Wechsler Adult Intelligence Scale, revised; WAIS-R) was examined in healthy controls (n=166). A total of 28 SNPs, including nine novel SNPs, were identified. No significant effects on transcriptional activity were observed for SNPs in the promoter region. A significant allelic association was found between several SNPs and bipolar disorder (for SNP23 at the 3' regulatory region; odds ratio 1.48, 95% confidential interval 1.16-1.88, P=0.0015). However, such an association was not detected for schizophrenia or depression. Significant differences were observed between SNP23 and attention/concentration sub-scale score of WMS-R (P=0.016) and verbal IQ (P<0.001). Genetic variation of the hNP gene may contribute to molecular mechanisms of bipolar disorder and some aspects of memory and intelligence.

Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling.

Disrupted-in-schizophrenia 1 (DISC1), identified in a pedigree with a familial psychosis with the chromosome translocation (1:11), is a putative susceptibility gene for psychoses such as schizophrenia and bipolar disorder. Although there are a number of patients with major depressive disorder (MDD) in the family members with the chromosome translocation, the possible association with MDD has not yet been studied. We therefore performed an association study of the DISC1 gene with MDD and schizophrenia. We found that Cys704 allele of the Ser704Cys single-nucleotide polymorphism (SNP) was associated with an increased risk of developing MDD (P=0.005, odds ratio=1.46) and stronger evidence for association in a multi-marker haplotype analysis containing this SNP (P=0.002). We also explored possible impact of Ser704Cys on brain morphology in healthy volunteers using MR imaging. We found a reduction in gray matter volume in cingulate cortex and a decreased fractional anisotropy in prefrontal white matter of individuals carrying the Cys704 allele compared with Ser/Ser704 subjects. In primary neuronal culture, knockdown of endogenous DISC1 protein by small interfering RNA resulted in the suppression of phosphorylation of ERK and Akt, whose signaling pathways are implicated in MDD. When effects of sDISC1 (Ser704) and cDISC1 (Cys704) proteins were examined separately, phosphorylation of ERK was greater in sDISC1 compared with cDISC1. A possible biological mechanism of MDD might be implicated by these convergent data that Cys704 DISC1 is associated with the lower biological activity on ERK signaling, reduced brain gray matter volume and an increased risk for MDD.

The Gem interacting protein (GMIP) gene is associated with major depressive disorder.

Major depressive disorder (MDD) is a mood disorder with a significant heritable component. Structural neuronal impairment has been considered to be implicated in MDD, as it leads to brain morphological alterations such as hippocampal atrophy. The Gem interacting protein, GMIP, is a novel Rho GTPase-activating protein known to play important roles in neurite growth and axonal guidance. We examined the GMIP gene for possible association in a Japanese sample of 164 patients with MDD and 164 controls matched for sex. We found a significant association with MDD for one single nucleotide polymorphism (SNP) (-525G/A) located on the 5'-upstream region of the GMIP gene (p=0.039, odds ratio 1.66, 95% CI 1.05-2.69) and stronger evidence for association in a multimarker haplotype analysis (p=0.004). We then performed a promoter-luciferase reporter assay; the promoter activity for -525A allele, which was in excess in the MDD patients, was significantly decreased compared with the -525G allele in transient transfection experiments using three types of cell lines. Our results suggest that genetic variations in the GMIP gene can confer susceptibility to MDD, and the associated promoter SNP might play a role in the transcriptional regulation of the GMIP gene. Further study needs to be undertaken to validate the association between the GMIP gene and MDD.

The breakpoint cluster region gene on chromosome 22q11 is associated with bipolar disorder.

BACKGROUND: Although the pathogenesis of bipolar disorder remains unclear, heritable factors have been shown to be involved. The breakpoint cluster region (BCR) gene is located on chromosome 22q11, one of the most significant susceptibility loci in bipolar disorder linkage studies. The BCR gene encodes a Rho GTPase activating protein, which is known to play important roles in neurite growth and axonal guidance. METHODS: We examined patients with bipolar disorder (n = 171), major depressive disorder (n = 329) and controls (n = 351) in Japanese ethnicity for genetic association using eleven single nucleotide polymorphisms (SNPs), including a missense one (A2387G; N796S), in the genomic region of BCR. RESULTS: Significant allelic associations with bipolar disorder were observed for three SNPs, and associations with bipolar II disorder were observed in ten SNPs including N796S SNP (bipolar disorder, p = .0054; bipolar II disorder p = .0014). There was a significant association with major depression in six SNPs. S796 allele carriers were in excess in bipolar II patients (p = .0046, odds ratio = 3.1, 95% CI 1.53-8.76). Furthermore, we found a stronger evidence for association with bipolar II disorder in a multi-marker haplotype analysis (p = .0002). CONCLUSIONS: Our results suggest that genetic variations in the BCR gene could confer susceptibility to bipolar disorder and major depressive disorder.

Season of birth in Japanese patients with schizophrenia.

A number of North American and European studies have observed a higher proportion of winter births in schizophrenia patients. Fewer studies have investigated this issue in Asian populations, and the findings are not as consistent as in the studies of Western populations. A statistically significant excess of winter births has not been observed in Japanese or Korean studies, while some of the studies found a decreased number of summer births among their patients. We further investigated the issue in Japanese patients with schizophrenia (n=2985). No significant excess of winter births was observed. Spearman correlation between schizophrenia births and ambient temperature was not significant. However, a decrease in the summer births was found, consistent with most of the previous Japanese studies. When analyzed by gender, a decrease in summer births was found in males, but not in females. In addition, a trend towards an increase in winter births was observed and Spearman correlation between low ambient temperature and schizophrenia births was significant in male subjects. More significant seasonality of birth in male patients than in female patients might be related to more susceptibility to pre- or perinatal disturbances in neurodevelopment in males than in females.