[Show abstract][Hide abstract] ABSTRACT: PiggyBac transposable element derived 1 (PGBD1) encodes a molecule involved in epigenetic mechanisms that have been implicated in Alzheimer's disease (AD), and recent genome-wide association studies and meta-analyses have indicated that a single nucleotide polymorphism (SNP), rs3800324, in PGBD1 could be associated with AD and the age of onset. However, no Japanese patients were examined in these studies. The aim of the present study was to replicate the previous finding in Japanese AD cases.
We performed a case-control study (211 cases and 156 controls) to investigate the association between PGBD1 and Japanese AD using 4 tag SNPs including rs3800324.
Single SNP and haplotype analysis showed no association between AD and age of onset, whereas genotypic and allelic frequencies of the ∊4 of apolipoprotein E (APOE) showed an association with AD as expected.
In Japanese AD, we observed no influence of PGBD1, as either a risk factor or a modifier, even though APOE was associated with AD in this population.
[Show abstract][Hide abstract] ABSTRACT: Recent GWAS demonstrated an association between candidate genes located at region 6p22.1 and schizophrenia. This region has been reported to house certain candidate SNPs, which may be associated with schizophrenia at HIST1H2BJ, PRSS16, and PGBD1. These genes may presumably be associated with pathophysiology in schizophrenia, namely epigenetics and psychoneuroimmunology. A three-step study was undertaken to focus on these genes with the following aims: (1) whether these genes may be associated in Japanese patients with schizophrenia by performing a 1st stage case-control study (514 cases and 706 controls) using Japanese tagging SNPs; (2) if the genetic regions of interest for the disease from the 1st stage of analyses were found, re-sequencing was performed to search for new mutations; (3) finally, a replication study was undertaken to confirm positive findings from the 1st stage were reconfirmed using a larger number of subjects (2,583 cases and 2,903 controls) during a 2nd stage multicenter replication study in Japan. Genotyping was performed using TaqMan PCR method for the selected nine tagging SNPs. Although three SNPs situated at the 3' side of PGBD1; rs3800324, rs3800327, and rs2142730, and two-window haplotypes between rs3800327 and rs2142730 showed positive associations with schizophrenia, these associations did not have enough power to sustain significance during the 2nd stage replication study. In addition, re-sequencing for exons 5 and 6 situated at this region did not express any new mutations for schizophrenia. Taken together these results indicate that the genes HIST1H2BJ, PRSS16, and PGBD1 were not associated with Japanese patients with schizophrenia.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2012; 159B(4):456-64. DOI:10.1002/ajmg.b.32049 · 3.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Disrupted glutamatergic neurotransmission and cognitive functions are key components in the pathophysiology of schizophrenia. Changes in levels of serum/plasma glutamatergic amino acids, such as glutamate, glycine, and L- and D-serine may be possible clinical markers. Following our recent findings that peripheral blood levels of endogenous glycine, alanine, and especially D-serine may reflect the degree/change in symptoms in schizophrenia, here we investigated whether these plasma amino acid levels may also reflect the status of cognitive functions in schizophrenia.
One hundred eight Japanese patients with schizophrenia were evaluated with cognitive assessment batteries at the time that plasma glutamatergic amino acid levels were measured using high-performance liquid chromatography. For analyzing cognitive functions, batteries for reflection prefrontal cortex cognitive functions, verbal fluency tests, the Stroop test, and the digit span forward and backward tests were administered.
Results failed to show a relationship between any plasma glutamatergic amino acid level and cognitive batteries.
Our results suggest that plasma glutamatergic amino acid levels may be significant biological markers that reflect the condition or a dramatic change at the time of testing, especially in severely affected patients, but they do not reflect cognitive function.
The International Journal of Psychiatry in Medicine 01/2012; 44(1):17-27. DOI:10.2190/PM.44.1.b · 0.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Increasing clinical attention has been focused on cardiac sympathetic denervation for the differential diagnosis of dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) with the development of [123I] metaiodobenzylguanidine (MIBG) scintigraphy. Decreased MIBG uptake, which reflects cardiac sympathetic denervation, has been detected in DLB, but not in AD. However, the time course of detected cardiac sympathetic degeneration is poorly understood in DLB. Herein, the authors report two patients with a clinical diagnosis of amnestic mild cognitive impairment (MCI) who had cardiac sympathetic denervation, detected by cardiac (123)I-MIBG scintigraphy, without the core clinical features of DLB. One amnestic MCI patient had nocturnal dream enactment behavior, consistent with clinically probable REM sleep behavior disorder (RBD), and converted to probable DLB with the development of recurrent visual hallucination and spontaneous parkinsonism two years after MCI is diagnosed. The other amnestic MCI patient exhibited occipital metabolic reduction on [18F]-fluoro-d-glucose (FDG) positron emission tomography (PET) scan, which is the preferentially affected region in DLB patients, although she had no core or suggestive clinical features of DLB. Both patients had abnormal findings on electrocardiogram at annual health checkups despite having no cardiac-related symptoms. Detailed clinical examinations, including angiography and echocardiogram, revealed no overt etiology, supporting the idea that cardiac sympathetic denervation is due to underlying Lewy body disease. The clinical courses of these patients suggest that (123)I-MIBG cardiac scintigraphy is useful for the detection of DLB in the predementia phase, even before core clinical features appear.
Journal of the neurological sciences 11/2011; 315(1-2):115-9. DOI:10.1016/j.jns.2011.11.012 · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Disrupted glutamatergic neurotransmission may be a pathophysiological feature in the brains from patients with schizophrenia, and glutamatergic amino acids including d-serine have been found to be involved in pathophysiology. Endogenous and exogenous d-serine have shown potential as biological markers for the pathophysiology of schizophrenia and especially as a therapeutic strategy in treatment-resistant schizophrenia (TRS). This is the first study investigating whether SLC7A10, a d-serine transporter gene, is associated with schizophrenia in Japanese patients.We investigated the association between schizophrenia in Japanese patients with SLC7A10 using six tag single nucleotide polymorphisms (SNPs). Results failed to show any association between Japanese schizophrenia and each individual SNP or with two-, three-, or four-window haplotype analyses. We also investigated whether SLC7A10 contributes to TRS in Japanese participants. Results showed no association.In conclusion, SLC7A10 had no apparent degree of association with schizophrenia as a candidate susceptibility gene in the disease per se.Highlights► SCL7A10, a D-serine transporter might be a susceptibility gene for schizophrenia. ► We examined whether SLC7A10 were related to Japanese schizophrenia. ► SLC7A10 had no association with Japanese patients with schizophrenia.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 08/2011; 35(8):1965-1968. DOI:10.1016/j.pnpbp.2011.08.012 · 4.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Treating the 20-30% of patients with schizophrenia whose symptoms are resistant to antipsychotic treatment, a condition known as treatment-resistant schizophrenia (TRS), can be problematic. Recently, an association between Disrupted-in-Schizophrenia-1 (DISC1), a candidate susceptibility gene for schizophrenia, and TRS was reported. Associations between three missense SNPs, rs3738401 (Q264R), rs6675281 (L607F), and rs821616 (S704C) in DISC1, especially rs3738401, showed strong significance. Thus, the main aim of our current study was to examine if the reported possible functional polymorphisms in DISC1 were related to Japanese TRS. First, DISC1 was re-investigated in 485 Japanese patients with schizophrenia and 660 healthy controls with a case-control study using four candidate SNPs, rs751229, rs3738401, rs821597, and rs821616. DISC1 was not associated with schizophrenia in the Japanese population. Second, we investigated whether these SNPs contributed to TRS in 127 inpatients with schizophrenia (35 patients; TRS and 92 patients; non-TRS). The genotypic distributions of these four SNPs were not significantly different between TRS and non-TRS in either genotypic or recessive models of minor alleles. In addition, clinical variables, such as improvement in clinical symptoms, duration of hospitalization, and total antipsychotics dose amounts, were not different among the genotypes of these SNPs. Taken together, results showed that DISC1 had no apparent degree of association with Japanese patients with schizophrenia as a candidate susceptibility gene for disease per se or TRS.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 03/2011; 35(2):636-9. DOI:10.1016/j.pnpbp.2011.01.011 · 4.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia is a major psychiatric disorder with complex genetic, environmental, and psychological causes, and oxidative stress may be involved in the pathogenesis of the disease. Glutathione (GSH), one of the main cellular non-protein antioxidants and redox regulators, and altered GSH levels have been reported in various regions in patients with schizophrenia. Three enzymes are responsible for GSH synthesis: glutamate cysteine ligase modifier (GCLM), glutamate cysteine ligase catalytic subunit (GCLC), and glutathione synthetase (GSS). Previously, positive associations between GCLM and schizophrenia were reported in Europeans, but not in the Japanese population. Thus, in this study, we investigated the association between the GSH synthesis genes (GCLM, GCLC, and GSS) and schizophrenia in Japanese individuals.
Seventeen single-nucleotide polymorphisms (SNP) in GCLM, GCLC, and GSS were genotyped in 358 patients with schizophrenia and in 359 controls.
No SNP showed a significant association between their allelic or genotypic frequencies and schizophrenia. Case-control haplotype association analysis using windows of two or three SNP showed no significant associations with schizophrenia. The case-control haplotype analyses based on the ascertained linkage disequilibrium blocks also showed no significant associations in any genes with schizophrenia.
The three primary GSH synthesis genes do not have an apparent degree of association with schizophrenia in the Japanese population.