Tatsuyuki Muratake

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.

No association between the brain-derived neurotrophic factor gene and schizophrenia in a Japanese population.

Brain-derived neurotrophic factor (BDNF) plays important roles in the survival, maintenance and growth of neurons. Several studies have indicated that BDNF is likely to be related to the pathogenesis of schizophrenia. Recent genetic analyses have revealed that BDNF gene polymorphisms are associated with schizophrenia, although contradictory negative findings have also been reported. To assess whether three BDNF gene polymorphisms (rs988748, C132T and rs6265) could be implicated in vulnerability to schizophrenia, we conducted a case-control association analysis (349 patients and 423 controls) in Japanese subjects. We found no association between these BDNF gene polymorphisms and schizophrenia using both single-marker and haplotype analyses. The results of the present study suggest that these three BDNF gene polymorphisms do not play major roles in conferring susceptibility to schizophrenia in a Japanese population. However, further studies assessing the associations between these BDNF gene polymorphisms and schizophrenia should be performed in several other ethnic populations.

Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2B5

We report of a woman aged 52 years born to consanguineous parents and seeking treatment for progressive dementia and delusion. Neurologic examination revealed dementia and emotional instability, indifference, and confabulation. There was also mild spasticity of the bilateral lower limbs. MRI revealed diffuse white matter hyperintensity on T2-weighted images accompanied by hypointense areas on fluid-attenuated inversion recovery images. A homozygous missense mutation was identified in EIF2B5.

A psychometrically derived impulsive trait related to a polymorphism in the serotonin transporter gene‐linked polymorphic region (5‐HTTLPR) in a japanese nonclinical population: Assessment by the barratt impulsiveness scale (BIS)

Although a number of studies have shown that human impulsive traits are associated with indices of central serotonin function, few researchers have investigated the relationship between a polymorphism in the serotonin transporter gene‐linked region (5‐HTTLPR) and a psychometrically derived impulsive trait. We determined the 5‐HTTLPR polymorphism in 123 employed Japanese male adults using the polymerase chain reaction. The distribution of allelic frequency was determined and also investigated the relationship of the 5‐HTTLPR polymorphism to a impulsive trait as measured by the Barratt Impulsiveness Scale, 11th version (BIS‐11). The distribution of allelic frequency was found to be almost identical to that previously reported in Japanese (the frequency for the long (L)/L, L/short (S), and S/S genotypes was: 3, 28, and 68%, respectively). In a comparison between the genotype groups, the S/S genotype group significantly higher scored for the total BIS‐11 and the subscale attentional impulsiveness than the L/S + L/L genotype group. These findings suggest that individuals with a homozygous S‐allele may be more impulsive than those with the other genotype.

Synergistic association of mitochondrial uncoupling protein (UCP) genes with schizophrenia

Many studies suggest that mitochondrial dysfunction is involved in the pathophysiology of schizophrenia. We performed a case‐control study using tag SNPs in the mitochondrial uncoupling protein genes, UCP2, UCP4, and BMCP1/UCP5, to investigate their association with schizophrenia. These neuronal UCPs are expressed in various brain tissues and may exert a neuroprotective effect against increased oxidative stress. We found modest associations between schizophrenia and the four tag SNPs, rs660339 (odds ratio (OR) = 1.330; P = 0.0043) and rs649446 (OR = 0.739; P = 0.0069) in UCP2, and rs10807344 (OR = 0.622; P = 0.0029) and rs2270450 (OR = 0.704; P = 0.0043) in UCP4, all of which were statistically significant even after correcting for multiple comparisons. Moreover, we found a statistically significant synergistic interaction between UCP2 and UCP4 by using the multifactor dimensionality reduction (MDR) method. The synergistic interaction was also confirmed by the logistic regression analysis, where the maximal OR was obtained when the risk alleles at rs660339 and rs10807344 were simultaneously homozygous. Individuals possessing homozygous risk alleles at these two loci have a 7.6‐fold risk of developing schizophrenia compared with those of minimal OR. Our findings suggest that UCP2 and UCP4 have a modest but important involvement in the genetic etiology of schizophrenia. This is the first report of the association between schizophrenia and neuronal UCPs.

Support for association of the PPP3CC gene with schizophrenia

Calcineurin is a calcium-dependent protein phosphatase that plays an important role in cellular responses and calcium signal transduction. Several studies have suggested that calcineurin is one of the key molecules in signal transduction in the brain and that dysfunction of calcineurin signaling could be linked to schizophrenia. Calcineurin is a heteromeric protein complex consisting of a catalytic subunit (calcineurin A) and a regulatory subunit (calcineurin B). PPP3CC encodes the calcineurin g-catalytic subunit and is located on chromosome 8p21.3 within a few cM of markers reported to be linked to schizophrenia. Gerber et al. reported genetic associations of the PPP3CC gene with schizophrenia in populations from the United States and South Africa. However, only one replication study has been published, and these associations were not confirmed in 457 Japanese schizophrenic patients and 429 control subjects. HapMap data indicated that a haplotype block spans almost the entire PPP3CC region in Japanese and European populations. The single nucleotide polymorphism (SNP) haplotype reported to be associated with schizophrenia by Gerber et al. is located in the haplotype block. Therefore, we examined the associations in a large case–control study of 1645 schizophrenic patients and 1673 control subjects. This sample size has a power > 0.98 to replicate the haplotypic association with the same magnitude as that reported by Gerber et al., assuming an a value = 0.05, two-tailed, a haplotype relative risk of 1.23, and haplotype frequency of 0.26 or effect size of 0.1. The haplotype frequency in the Japanese population was reported by Kinoshita et al. All subjects were of Japanese descent and were recruited from the main island of Japan. The study included 1645 unrelated patients with schizophrenia (mean age7s.d., 48.2714.5 years; 899 men and 745 women) diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Control subjects were 1673 mentally healthy unrelated subjects (age, 47.9714.3, 886 men and 787 women) without self-reported family histories of mental illness within second-degree relatives. The subjects studied by Kinoshita et al. were not included in the present study. The present study was approved by the Ethics Committees of the University of Tsukuba, Niigata University, Fujita Health University, Nagoya University, Okayama University and Teikyo University and all participants provided written informed consent. To rule out population stratification between patients and controls in the present study, 35 SNPs that are not in linkage disequilibrium (LD) with each other were genotyped in all samples and analyzed with the STRUCTURE program 2.0. No stratification was observed. We genotyped five SNPs. SNP1 (rs10108011, CC21 in Gerber et al.) and SNP2 (rs2461491, CCS3 in Gerber et al.) were selected because Gerber et al. reported nominally significant allelic association of these SNPs with schizophrenia. SNP4 (rs2449340), SNP3 (rs2461490) and SNP5 (rs1116085) were genotyped to distinguish common haplotypes with frequencies X5% in the haplotype block based on HapMap data of the Japanese population. SNPs were genotyped with the TaqMan SNP Genotyping Assay (Applied Biosystems, Foster City, CA, USA) and ABI PRISM 7900HT Sequence Detection System (Applied Biosystems). Deviation from predicted Hardy–Weinberg frequency was examined by w-test. Individual allelic and genotypic associations were examined by Fisher’s exact test. LD between polymorphisms and haplotypic associations were evaluated with Haploview software version 3.32. To deal with multiple testing, allelic associations were evaluated by permutation tests implemented in Haploview. The genotype distributions were evaluated by the Cochran–Armitage test without correction for multiple testing. The genotype and allele distributions of the five SNPs in the patient group and control group are shown in Table 1. Distributions of these SNPs did not differ significantly from Hardy–Weinberg equilibrium. All five SNPs showed nominally significant allelic associations with schizophrenia and permutation tests revealed significant allelic associations of SNP1 (P = 0.012), SNP3 (P = 0.005) and SNP4 (P = 0.013) with schizophrenia. The genotype distributions suggest that the minor allele of each SNP is likely to have an additive effect in the susceptibility to schizophrenia. These five SNPs are in LD; however, the LD is not complete. Therefore, these associations were not caused by a single SNP in the present study. As shown in Table 2, there were only two common haplotypes constructed from these SNPs. The most common haplotype in the control group was observed less frequently in the patient group (P = 0.034) and the second most common Molecular Psychiatry (2007) 12, 891–903 & 2007 Nature Publishing Group All rights reserved 1359-4184/07

No associations exist between five functional polymorphisms in the catechol -O-methyltransferase gene and schizophrenia in a Japanese population

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Genetic and expression analyses of FZD3 in schizophrenia

Catechol-O-methyltransferase (COMT) is one of the enzymes that degrade catecholamine neurotransmitters including dopamine. The COMT gene is located on 22q11.2, a common susceptibility locus for schizophrenia. Therefore, COMT is a strong functional and positional candidate gene for schizophrenia. A common functional polymorphism (rs4680, Val158Met) has been extensively tested for an association with schizophrenia, but with conflicting results. Recent studies indicate that if COMT is implicated in susceptibility to schizophrenia, this cannot be wholly accounted for by the Val158Met polymorphism. To assess this view, the authors conducted a case-control association study (399 patients with schizophrenia and 440 control subjects) for five functional polymorphisms (rs2075507, rs737865, rs6267, rs4680 and rs165599) in Japanese subjects. There were no significant associations found between the polymorphisms or haplotypes of COMT and schizophrenia. The present study shows that these five functional COMT polymorphisms do not play a major role in conferring susceptibility to schizophrenia in Japanese.

Lack of association between the interleukin‐1 gene complex and schizophrenia in a Japanese population

BACKGROUND Wnt signaling plays important roles in neurodevelopmental processes. Frizzled is a receptor of Wnt protein, and the Frizzled 3 (FZD3) gene was recently reported to be associated with schizophrenia. Our study attempted to confirm associations between FZD3 and schizophrenia in Japanese family and case-control samples. METHODS Genetic associations were evaluated using family-based transmission tests (212 families, 643 subjects) and case--control analysis (540 schizophrenia patients, 540 control sample). Six single nucleotide polymorphisms (SNPs) on the FZD3 locus were genotyped, and levels of FZD3 mRNA expression in postmortem brains were examined. RESULTS Neither family- nor population-based studies supported associations between FZD3 and schizophrenia. FZD3 expression was unaltered in schizophrenic brains. CONCLUSIONS Although two prior studies have reported associations using limited numbers of SNPs on FZD3, our intensive study failed to support any major contribution of FZD3 to schizophrenia susceptibility.

Failure to confirm the association between the FEZ1 gene and schizophrenia in a Japanese population

Abstract  Interleukin‐1 (IL1) is an inflammatory cytokine and exerts neurodegenerative effects in the brain. Several studies have indicated that IL1 is likely to be involved in the pathogenesis of schizophrenia. Recent genetic studies have revealed that the IL1 gene complex (IL,1 alpha, IL1, beta and IL1 receptor antagonist) was associated with schizophrenia, although contradictory findings have also been reported. To assess whether the IL1 gene complex was implicated in vulnerability to schizophrenia, the authors conducted a case‐control association study (416 patients with schizophrenia and 440 control subjects) for nine polymorphisms in Japanese subjects. The authors found no association between the IL1 gene complex polymorphisms and schizophrenia using either single‐marker or haplotype analyses. The results of the present study suggest that the IL1 gene complex does not play a major role in conferring susceptibility to schizophrenia in the Japanese population.