SAT-1 -1415T/C polymorphism and susceptibility to schizophrenia

Patients suffering from psychosis show increased blood and fibroblast total polyamine levels. Spermidine/spermine N1-acetyltransferase (SSAT-1) and its coding gene (SAT-1) are the main factors regulating polyamine catabolism. The aim of the present study was to examine the association between the SAT-1 -1415T/C single nucleotide polymorphism (SNP) and schizophrenia. A case-control design was used in order to compare the genotypes for the SNP between schizophrenia patients (n = 180, 83 females and 97 males), other non-psychotic psychiatric patients (n = 413, 256 females and 157 males), and healthy controls (n = 251, 101 females and 150 males).     

Association study between glutathione S-transferase P1 polymorphism and schizophrenia in the Korean population

This study is aimed to test the association between the coding sequence functional polymorphism (Ile105Val) of glutathione S-transferase P gene (GSTP1) and schizophrenia in the Korean population. Two hundred fourteen patients with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria and 110 healthy controls were enrolled in this study. Patients and controls were biologically unrelated age and sex-matched native Koreans. Genotyping for GSTP1 polymorphism was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). Genotype and allele distributions of GSTP1 polymorphism in patients with schizophrenia were not significantly different from those of the controls. Comparisons of clinical variables including Positive and Negative Syndrome Scale (PANSS), change of Brief Psychiatric Rating Scale (BPRS), number of admission, and onset age also were not different according to genotype distribution. The present study suggests that GSTP1 polymorphism may not confer susceptibility to development of schizophrenia in the Korean population.     

Genetic polymorphism in the DNA repair gene XRCC1 and susceptibility to schizophrenia

The X-ray repair cross-complementation group 1 (XRCC1) protein plays an important role in base excision repair. A high level of XRCC1 mRNA and/or protein has been found in rat and baboon brains. An exon 10 variant at codon 399 of XRCC1 leads to an Arg to Gln amino acid change. The 399Gln allele is associated with an increased risk of several types of cancers, increased DNA adducts and chromosomal changes; therefore, it appears that the 399Gln allele may alter the role of the XRCC1 protein in DNA repair. The present case-control study was performed on 303 (223 males, 80 females) in-patients with chronic schizophrenia and 303 healthy blood donors matched to the patients by age (+/-5 years) and gender. The XRCC1 genotypes were determined using a PCR-based method. Heterozygosity (OR=1.48, 95% CI: 1.05-2.09) and homozygosity (OR=2.00, 95% CI: 1.17-3.42) for the Gln399 allele increased the risk of schizophrenia. There was a significant linear trend in risk associated with zero, one, and two 399Gln alleles. The present finding indicates that XRCC1 is a candidate gene for susceptibility to schizophrenia.     

Association between three genetic polymorphisms of glutathione S-transferase Z1 (GSTZ1) and susceptibility to bipolar disorder

The association between polymorphisms of glutathione S-transferase Z1 (GSTZ1) and susceptibility to bipolar disorder (BPD) is investigated. This study was performed on 228 BPD patients and 234 control subjects. Among early-onset patients, the variant alleles of Glu32Lys and G-1002A increased BPD susceptibility. The haplotype "-1002G, 32Glu, 42Gly" versus the other haplotypes was significantly decreased among early-onset patients compared to controls (P=0.016).     

Support for genetic variation in neuregulin 1 and susceptibility to schizophrenia

Recently, it has been reported that genetic variants around the gene neuregulin 1 are associated with schizophrenia in an Icelandic sample. Of particular interest was the presence of a single-risk haplotype that was significantly over-represented in schizophrenic individuals compared to controls (15.4 : 7.5%, P=6.7 x 10(-6)). We have attempted to replicate this result in our large collection of 573 schizophrenia cases and 618 controls. We found that the risk haplotype was more common in cases than controls (9.5 : 7.5%; P=0.04), and especially in our subset of 141 cases with a family history of schizophrenia (11.6%; P=0.019). Our results therefore replicate the Icelandic findings in an out-bred Northern European population, although they suggest that the risk conferred by the haplotype is small.     

Genetic analysis of the DLGAP1 gene as a candidate gene for schizophrenia

Schizophrenia is a severe chronic mental disorder with high genetic components in its etiology. Several studies indicated that synaptic dysfunction is involved in the pathophysiology of schizophrenia. Postsynaptic synapse-associated protein 90/postsynaptic density 95-associated proteins (SAPAPs) constitute a part of the N-methyl-d-aspartate receptor-associated postsynaptic density proteins, and are involved in synapse formation. We hypothesized that genetic variants of the SAPAPs might be associated with schizophrenia. Thus, we systemically sequenced all the exons of the discs, large (Drosophila) homolog-associated protein 1 (DLGAP1) gene that encodes SAPAP1 in a sample of 121 schizophrenic patients and 120 controls from Taiwan. We totally identified six genetic variants, including five known SNPs (rs145691437, rs3786431, rs201567254, rs3745051 and rs11662259) and one rare missense mutation (c.1922A>G) in this sample. SNP- and haplotype-based analyses showed no association of these SNPs with schizophrenia. The c.1922A>G mutation that changes the amino acid lysine to arginine at codon 641 was found in one out of 121 patients, but not in 275 control subjects, suggesting it might be a patient-specific mutation. Nevertheless, bioinformatic analysis showed this mutation does not affect the function of the DLGAP1 gene and appears to be a benign variant. Hence, its relationship with the pathogenesis remains to be investigated.     

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

The discovery of genetic factors that contribute to schizophrenia susceptibility is a key challenge in understanding the etiology of this disease. Here, we report the identification of a novel schizophrenia candidate gene on chromosome 1q32, plexin A2 (PLXNA2), in a genome-wide association study using 320 patients with schizophrenia of European descent and 325 matched controls. Over 25,000 single-nucleotide polymorphisms (SNPs) located within approximately 14,000 genes were tested. Out of 62 markers found to be associated with disease status, the most consistent finding was observed for a candidate locus on chromosome 1q32. The marker SNP rs752016 showed suggestive association with schizophrenia (odds ratio (OR) = 1.49, P = 0.006). This result was confirmed in an independent case-control sample of European Americans (combined OR = 1.38, P = 0.035) and similar genetic effects were observed in smaller subsets of Latin Americans (OR = 1.26) and Asian Americans (OR = 1.37). Supporting evidence was also obtained from two family-based collections, one of which reached statistical significance (OR = 2.2, P = 0.02). High-density SNP mapping showed that the region of association spans approximately 60 kb of the PLXNA2 gene. Eight out of 14 SNPs genotyped showed statistically significant differences between cases and controls. These results are in accordance with previous genetic findings that identified chromosome 1q32 as a candidate region for schizophrenia. PLXNA2 is a member of the transmembrane semaphorin receptor family that is involved in axonal guidance during development and may modulate neuronal plasticity and regeneration. The PLXNA2 ligand semaphorin 3A has been shown to be upregulated in the cerebellum of individuals with schizophrenia. These observations, together with the genetic results, make PLXNA2 a likely candidate for the 1q32 schizophrenia susceptibility locus.     

Genetic polymorphism of paraoxonase 1 (PON1) and susceptibility to Parkinson''s disease

Toxicologists have thought that the paraoxonase (PON) enzyme polymorphism might contribute to effects of pollutants and other environmental chemicals on susceptibility to cancer, birth defects and Parkinson's disease (PD). We studied a biallelic PON1 polymorphism at codon 192 (A and B alleles) in 166 patients with sporadic idiopathic PD. The frequency of the B (Arg) allele of PON1 was significantly increased in patients with PD than in healthy controls (χ²=8.75, df=1, P<0.005). The relative risk of PD in homozygotes for the B allele was 1.60 fold higher than individuals with the A (Gln) allele (χ²=7.38, df=1, P<0.01). Our data suggest that environmental neurotoxins metabolized by PON1 might be responsible for neurodegeneration with aging and that the B (Arg) allele form might have genetic susceptibility to PD.     

Genetic regulation of Nrnx1 expression: an integrative cross-species analysis of schizophrenia candidate genes

Neurexin 1 (NRXN1) is a large presynaptic transmembrane protein that has complex and variable patterns of expression in the brain. Sequence variants in NRXN1 are associated with differences in cognition, and with schizophrenia and autism. The murine Nrxn1 gene is also highly polymorphic and is associated with significant variation in expression that is under strong genetic control. Here, we use co-expression analysis, high coverage genomic sequence, and expression quantitative trait locus (eQTL) mapping to study the regulation of this gene in the brain. We profiled a family of 72 isogenic progeny strains of a cross between C57BL/6J and DBA/2J (the BXD family) using exon arrays and massively parallel RNA sequencing. Expression of most Nrxn1 exons have high genetic correlation (r>0.6) because of the segregation of a common trans eQTL on chromosome (Chr) 8 and a common cis eQTL on Chr 17. These two loci are also linked to murine phenotypes relevant to schizophrenia and to a novel human schizophrenia candidate gene with high neuronal expression (Pleckstrin and Sec7 domain containing 3). In both human and mice, NRXN1 is co-expressed with numerous synaptic and cell signaling genes, and known schizophrenia candidates. Cross-species co-expression and protein interaction network analyses identified glycogen synthase kinase 3 beta (GSK3B) as one of the most consistent and conserved covariates of NRXN1. By using the Molecular Genetics of Schizophrenia data set, we were able to test and confirm that markers in NRXN1 and GSK3B have epistatic interactions in human populations that can jointly modulate risk of schizophrenia.     

The C3435T polymorphism of MDR1 and susceptibility to adult glioma

INTRODUCTION: The multidrug resistance-1 (MDR1) gene encodes a pump that prevents potentially carcinogenic substances from crossing the blood-brain barrier. We compare adult glioma cases and controls for the C3435T polymorphism that has been associated with reduced MDR1 expression. METHODS: Adult glioma in the San Francisco Bay area and population-based controls were identified between 1991-1994 and 1997-1999. Genotyped cases (n = 458) and controls (n = 528) were compared using logistic regression controlling for age, gender and ethnicity, with later stratification by ethnicity, gender and histology. RESULTS: With CC as the referent, the TT genotype was nonsignificantly less frequent among cases compared to controls (OR, 0.87; 95% CI: 0.6, 1.2). After stratification, only male glioblastoma was associated with TT genotype (OR, 0.51; 95% CI: 0.3, 1.0). CONCLUSIONS: Although the C3435T polymorphism does not appear to be associated with other types of glioma, we cannot rule out that this MDR1 polymorphism may be associated with glioblastoma among men.     

A polymorphism of the ABCA1 gene confers susceptibility to schizophrenia and related brain changes

Objective

The ATP-binding cassette transporter A1 (ABCA1) mediates cellular cholesterol efflux through the transfer of cholesterol from the inner to the outer layer of the cell membrane and regulates extracellular cholesterol levels in the central nervous system. Several lines of evidence have indicated lipid and myelin abnormalities in schizophrenia.

Method

Initially, we examined the possible association of the polymorphisms of the ABCA1 gene (ABCA1) with susceptibility to schizophrenia in 506 patients with schizophrenia (DSM-IV) and 941 controls. The observed association was then subject to a replication analysis in an independent sample of 511 patients and 539 controls. We further examined the possible effect of the risk allele on gray matter volume assessed with magnetic resonance imaging (MRI) in 86 patients with schizophrenia (49 males) and 139 healthy controls (47 males).

Results

In the initial association study, the 1587 K allele (rs2230808) was significantly more common in male patients with schizophrenia than in male controls. Although such a significant difference was not observed in the second sample alone, the increased frequency of the 1587 K allele in male patients remained to be significant in the combined male sample of 556 patients and 594 controls. Male schizophrenia patients carrying the 1587 K allele had a smaller amount of gray matter volume than those who did not carry the allele.

Conclusion

Our data suggest a male-specific association of the 1587 K allele of ABCA1 with susceptibility to schizophrenia and smaller gray matter volume in schizophrenia.     

N-乙酰基转移酶基因多态性与帕金森病遗传易患性关系的研究

目的 探讨N－乙酰基转移酶（NAT2）慢乙酰化等位基因和慢乙酰化基因型与帕金森病（Parkinson's disease,PD）的关系。方法 采取PCR－RFLP的方法，比较各100名原发性PD患者和健康人NAT2三个慢乙酰化等位基因M1，M2和M3的频率分布以及慢乙酰化基因型的频率分布差异。结果 在全部PD患者和健康对照组之间，NAT2慢乙酰化等基因和慢乙酰化基因型频率分布无显著差异。而在54名早发性PD患者（发病年龄＜55岁），M1，M2和M3的频率分布为7％，27％和22％，对照组为4％，16％和16％，两组差异显著（P＜0.05）。早发性PD患者和对照组慢乙酰化基因型的频率分布分别为24％和11％，两组差异显著（P＜0.05）。结论 NAT2慢乙酰化等位基因和慢乙酰化基因型可能与早发性PD有关。     

Effects of glutathione S-transferase M1 and T1 deletions on Parkinson's disease risk among a North African population

PurposeIn this study, the effects of glutathione S-transferase polymorphisms Mu1 (GSTM1) and glutathione S-transferase polymorphisms Theta1 (GSTT1) on Parkinson's disease (PD) risk factor were evaluated in a Tunisian population.MethodsThese polymorphisms were analyzed in 229 healthy Tunisian subjects and 64 Tunisian patients with PD, using a polymerase chain reaction (PCR). Statistical analysis was performed using SPSS 18.0. The relative associations between the GST genotypes and PD were assessed by calculating the odds ratios (ORs) and 95% confidence intervals (CIs).ResultsThe study results demonstrated that the individuals with GSTM1 [OR = 3.93, 95% CI: 1.98–7.92, P = 10^?6] and GSTT1 [OR = 5.45, 95% CI: 2.90–10.30, p = 10^?6] were statistically associated with the risk of PD. A significant association was also found between the individuals with both GSTM1/T1 null genotypes and PD risk [OR = 22.10, 95% CI: 6.99–73.75, P = 10^?6].ConclusionThese genotyping findings suggest that the absence of both GSTM1 and GSTT1 activity could be a contributory factor for the development of PD.     

谷胱甘肽S-转移酶P1~105基因多态性与高原环境下人体运动能力的关系

背景: 谷胱甘肽S-转移酶具有清除活性氧、提高机体抗氧化能力的作用。 目的：分析谷胱甘肽S-转移酶P1~105基因多态性与高原环境下人体运动能力的关联性。 设计、时间及地点：对照比较分析,于2007年在解放军体育进修学院完成。 对象：实验组86名高原登山运动员为在高原环境下具有较强的作业能力的特定人群,对照组为解放军体育学院随机选取的90名健康学员。 方法：采集86名高原登山运动员及90名健康学员的血样,提取基因组DNA,采用PCR-RFLP技术检测谷胱甘肽S-转移酶P1~105基因多态性,分别比较高原登山运动员与平原汉族对照人群间谷胱甘肽S-转移酶P1~105等位基因和基因型的分布。 主要观察指标：谷胱甘肽S-转移酶P1~105基因型的分布。 结果：共检测到谷胱甘肽S-转移酶P1~105基因3种基因型：变异杂合型(A/G)、变异纯合型(G/G)、野生基因型(A/A)。实验组谷胱甘肽S-转移酶P1~105的G等位基因、变异基因型(A/G+G/G)的频率皆明显低于对照组(P < 0.01)。以变异基因型作为暴露因素,求得OR＝2.19 ,95% CI=1.16~4.13,提示在高原环境下,与具有谷胱甘肽S-转移酶P1~105野生基因型人的运功能力比较,具有谷胱甘肽S-转移酶P1~105变异基因型人的运动能力下降了1.19倍。 结论：谷胱甘肽S-转移酶P1~105基因多态性与高原环境下人体运动能力相关,野生基因型表现出明显的运动优势。     

Genetic dissection of glutathione S-transferase omega-1: identification of novel downstream targets and Alzheimer 's disease pathways

Alzheimer's disease (AD) is affected by genetic factors. Polymorphisms in the glutathione S-transferase omega-1 (Gsto1) gene have been shown by genetic correlat...