Tohru Ohnuma

Genomewide High-Density SNP Linkage Analysis of 236 Japanese Families Supports the Existence of Schizophrenia Susceptibility Loci on Chromosomes 1p, 14q, and 20p

The Japanese Schizophrenia Sib-Pair Linkage Group (JSSLG) is a multisite collaborative study group that was organized to create a national resource for affected sib pair (ASP) studies of schizophrenia in Japan. We used a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the Illumina BeadArray linkage mapping panel (version 4) comprising 5,861 SNPs, to perform a genomewide linkage analysis of JSSLG samples comprising 236 Japanese families with 268 nonindependent ASPs with schizophrenia. All subjects were Japanese. Among these families, 122 families comprised the same subjects analyzed with short tandem repeat markers. All the probands and their siblings, with the exception of seven siblings with schizoaffective disorder, had schizophrenia. After excluding SNPs with high linkage disequilibrium, we found significant evidence of linkage of schizophrenia to chromosome 1p21.2-1p13.2 (LOD=3.39) and suggestive evidence of linkage to 14q11.2 (LOD=2.87), 14q11.2-q13.2 (LOD=2.33), and 20p12.1-p11.2 (LOD=2.33). Although linkage to these regions has received little attention, these regions are included in or partially overlap the 10 regions reported by Lewis et al. that passed the two aggregate criteria of a meta-analysis. Results of the present study--which, to our knowledge, is the first genomewide analysis of schizophrenia in ASPs of a single Asian ethnicity that is comparable to the analyses done of ASPs of European descent--indicate the existence of schizophrenia susceptibility loci that are common to different ethnic groups but that likely have different ethnicity-specific effects.

Gene expression of PSD95 in prefrontal cortex and hippocampus in schizophrenia.

A number of studies have suggested that disturbance in glutamatergic transmission in the cerebral cortex may underlie, or contribute to the pathophysiology of schizophrenia. In this study we examined expression of the postsynaptic density protein 95 (PSD95) mRNA in the prefrontal cortex and hippocampus in postmortem material from neuroleptic-treated schizophrenics and normal controls. PSD95 is known to bind to NMDA receptor subunits and is known to be involved in synaptic plasticity. In situ hybridization analysis showed that the expression of PSD95 was significantly decreased in Brodmann area 9 of the prefrontal cortex but not in the hippocampus. These results further implicate the prefrontal cortex in the pathophysiology of schizophrenia and suggest dysfunction of NMDA receptors in the schizophrenic cortex.

Genetic Association between SORL1 Polymorphisms and Alzheimer’s Disease in a Japanese Population

Background/Aims: It has recently been shown that the neuronal sortilin-related receptor (SORL1) plays an important role in the pathogenesis of Alzheimer’s disease (AD). Methods: To investigate whether variations around the SORL1 gene are associated with AD, 7 single-nucleotide polymorphisms (SNPs) were genotyped using TaqMan® technology with 180 AD patients and 130 age-matched controls. Results: Our results confirmed the strong linkage disequilibrium among the 7 SNPs studied. However, our study failed to detect any association between the SNPs and AD. We could not confirm any synergetic interaction between the SNPs and apolipoprotein E in our AD patients either. Conclusion: Further genetic studies are needed to clarify the relationship between the SORL1 gene and AD.

Association study of the G72 gene with schizophrenia in a Japanese population: A multicenter study

G72 is one of the most widely tested genes for association with schizophrenia. As G72 activates the D-amino acid oxidase (DAO), G72 is termed D-amino acid oxidase activator (DAOA). The aim of this study is to investigate the association between G72 and schizophrenia in a Japanese population, using the largest sample size to date (1774 patients with schizophrenia and 2092 healthy controls). We examined eight single nucleotide polymorphisms (SNPs), which had been associated with schizophrenia in previous studies. We found nominal evidence for association of alleles, M22/rs778293, M23/rs3918342 and M24/rs1421292, and the genotype of M22/rs778293 with schizophrenia, although there was no association of allele or genotype in the other five SNPs. We also found nominal haplotypic association, including M15/rs2391191 and M19/rs778294 with schizophrenia. However, these associations were no longer positive after correction for multiple testing. We conclude that G72 might not play a major role in the risk for schizophrenia in the Japanese population.

No genetic association between PCSK9 polymorphisms and Alzheimer's disease and plasma cholesterol level in Japanese patients.

SummaryGenetic mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene on the chromosome 1p cause susceptibility to autosomal dominant hypercholesterolemia (Abifadel et al., 2003; Leren, 2004; Timms et al., 2004). Variants of PCSK9 encoding neural apoptosis regulated convertase-1

Genetic evidence for association between NOTCH4 and schizophrenia supported by a GWAS follow-up study in a Japanese population.

Genetic evidence for association between NOTCH4 and schizophrenia supported by a GWAS follow-up study in a Japanese population

No Genetic Association between the Myeloperoxidase Gene –463 Polymorphism and Estrogen Receptor-α Gene Polymorphisms and Japanese Sporadic Alzheimer’s Disease

Myeloperoxidase (MPO) presence has been demonstrated in microglia associated with senile plaques and contributes to Alzheimer’s disease (AD) pathology through oxidation-induced damage. MPO activity is normally higher in women than in men. Additionally, a functional biallelic (G/A) polymorphism in the promoter region (–463) of the MPO gene has been associated with a gender-specific risk factor for AD, but reports of this association have been inconsistent. Furthermore, estrogen is known to enhance MPO activity in myeloid cells and increases the amount of MPO in plasma. Recently, estrogen replacement therapy has been reported to reduce the risk of developing AD and to help maintain cognitive function in patients with AD. In the current study, we analyzed the MPO –463 polymorphism and two estrogen receptor-α polymorphisms in 205 Japanese sporadic AD patients and 92 controls. The results suggest that there is no significant difference in the genotypic frequencies and allelic frequencies of the MPO –463 polymorphism and the estrogen receptor-α polymorphisms between the Japanese sporadic AD group and the control group.

Association between DNA Methylation of the BDNF Promoter Region and Clinical Presentation in Alzheimer's Disease

Background/Aims: In the present study, we examined whether DNA methylation of the brain-derived neurotrophic factor (BDNF) promoter is associated with the manifestation and clinical presentation of Alzheimers disease (AD). Methods: Of 20 patients with AD and 20 age-matched normal controls (NCs), the DNA methylation of the BDNF promoter (measured using peripheral blood samples) was completely analyzed in 12 patients with AD and 6 NCs. The resulting methylation levels were compared statistically. Next, we investigated the correlation between the DNA methylation levels and the clinical presentation of AD. Results: The total methylation ratio (in %) of the 20 CpG sites was significantly higher in the AD patients (5.08 ± 5.52%) than in the NCs (2.09 ± 0.81%; p < 0.05). Of the 20 CpG sites, the methylation level at the CpG4 site was significantly higher in the AD subjects than in the NCs (p < 0.05). Moreover, the methylation level was significantly and negatively correlated with some neuropsychological test subscores (registration, recall, and prehension behavior scores; p < 0.05). Conclusion: These results suggest that the DNA methylation of the BDNF promoter may significantly influence the manifestation of AD and might be associated with its neurocognitive presentation.

Genetic association between matrix metalloproteinase MMP-9 and MMP-3 polymorphisms and Japanese sporadic Alzheimer's disease.

Recent studies suggested that matrix metalloproteinases (MMPs) might play an important role in the pathophysiology of Alzheimers disease (AD). MMP-9 and MMP-3 are reported to degrade amyloid beta and have several functional polymorphisms associated with other common diseases. Four common polymorphisms in each of MMP-9 and MMP-3 were examined in AD cases and normal control individuals. Common polymorphisms of MMP-9, rs3918248, rs2664538, rs2250889 and rs2274756 showed no association with risk for AD. We observed strong linkage disequilibrium (LD) between rs2664538 and rs2250889 in our Japanese samples. The polymorphisms of MMP-3; 5A/6A insertion polymorphism in the promoter, rs3025079, rs520540 and rs679620 also did not influence risk for AD. LD of the 5A/6A polymorphism with rs679620 was relatively strong. These results suggest that the common polymorphisms of MMP-9 and MMP-3 investigated here are not associated with AD.

Association analysis of glycine- and serine-related genes in a Japanese population of patients with schizophrenia.

Differences in the levels of the glutamate-related amino acids glycine and serine in brain/plasma between schizophrenic patients and normal subjects and changes in the plasma concentrations of these amino acids according to the clinical course have been reported. It has been hypothesized that glycine and serine metabolism may be altered in schizophrenia. In fact, some genes related to the metabolism of these amino acids have been suggested to be candidate genes for schizophrenia. Thus, we performed a genomic case-control analysis of amino acid metabolism-related genes in Japanese patients with schizophrenia. Case-control genetic association analysis of PHGDH, SHMT1, SRR, and DAO was performed. In addition, the effect of the various genotypes resulting from these four genes on changes in plasma amino acid levels in schizophrenia was assessed. The genetic case-control analysis showed that no individual single-nucleotide polymorphism (SNP) in any of the four genes was associated with schizophrenia; only the two (rs3918347-rs4964770, P=0.0009) and three (rs3825251-rs3918347-rs4964770, P=0.002) SNP-based haplotype analysis of the DAO gene showed an association with schizophrenia even after correction for multiple testing. None of the genotypes studied was associated with changes in the plasma glycine and l- and d-serine levels during the schizophrenic clinical course. The DAO gene may be a susceptibility locus for schizophrenia.