Association of promoter variants of human dopamine transporter gene with schizophrenia in Han Chinese.

OBJECTIVE: Although dopamine was implicated in the etiology of schizophrenia, the human dopamine transporter gene (DAT1; SLC6A3) has not consistently been associated with schizophrenia. The purpose of this study was to examine whether six polymorphisms within the DAT1 gene are associated with schizophrenia. METHODS: Six polymorphisms of the DAT1 gene (3 SNPs [rs6413429, rs2652511, and rs2975226] in the promoter region, one SNP [rs6347] in exon 9, and one SNP [rs27072]/one variable number tandem repeat [VNTR] in exon 15) were analyzed in 352 Chinese patients with schizophrenia and in 311 healthy controls. Pretreatment psychopathology was assessed using the Positive and Negative Syndrome Scale in a subset of 160 hospitalized schizophrenia patients who were drug-free or drug-naïve. RESULTS: A statistically significant difference in two polymorphisms (rs2652511 and rs2975226) and a promoter region haplotype (rs2652511, rs2975226, and rs6413429) was found between patients and healthy controls. No association with schizophrenia was found for other polymorphisms and another haplotype (3' region). Symptoms severity (PANSS global, positive, negative and general symptoms scores) was similar regardless of DAT1 polymorphism. CONCLUSION: The promoter region of the DAT1 gene may play a role in increasing susceptibility to schizophrenia, but does not affect the severity of psychotic symptoms in Han Chinese.

Brain-derived neurotrophic factor Val66Met polymorphism: association with psychopathological symptoms of schizophrenia?

Brain-derived neurotrophic factor (BDNF) has been proposed as a risk factor for schizophrenia, but no consistent association between BDNF Val66Met polymorphism and schizophrenia has been established. Therefore, analyses with larger sample sizes and better methodology are needed. To examine whether BDNF Val66Met polymorphism is associated with schizophrenia, schizophrenia patients (n=251) and healthy volunteers (n=284) were recruited for a case-control analysis. Pretreatment psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) in a subset of 125 hospitalized schizophrenia patients who were drug-free or drug-naive. Genotyping was performed using polymerase chain reaction, restriction fragment length polymorphism (RFLP), and direct screening techniques. With the exception of nominally significant associations between BDNF Val66Met variation and PANSS total, negative, or general scores, no association between the BDNF Val66Met polymorphism and schizophrenia was found. However, this polymorphism may reduce psychopathology, in particular negative symptoms, in schizophrenia.

Association of monoamine oxidase A (MAOA) polymorphisms and clinical subgroups of major depressive disorders in the Han Chinese population.

It has been proposed that an MAOA abnormality may be an important factor in the development of major depressive disorder (MDD). Various polymorphisms of the MAOA gene have been investigated for possible associations with mood disorders, but results have been inconsistent. The goal of the present study was to investigate whether polymorphisms of the MAOA gene are associated with MDD or alternatively with different clinical subgroups of MDD. A total of 590 Han Chinese subjects in Taiwan (312 controls and 278 MDD patients) were recruited. Among the males, there were no associations with MAOA polymorphisms. Among the females, an association was found between MAOA polymorphisms and severe MDD (P=0.041 for uVNTR and 0.017 for EcoRV (rs1137070), respectively). However, in analyses of haplotype frequencies and multiple logistic regression, MAOA polymorphisms were not associated with either MDD or its subgroups. The results suggest that MAOA polymorphisms do not play a major role in the pathogenesis of MDD or its subgroups. However, a potential role for a minor association with some specific subgroups and with different ethnic samples needs to be explored further.

Neither single-marker nor haplotype analyses support an association between monoamine oxidase A gene and bipolar disorder.

Monoamine oxidase A (MAOA) abnormality has been suggested as a crucial factor in the pathogenesis of mood disorder, because MAOA is associated with the metabolism of monoamines such as serotonin and norepinephrine. Various MAOA gene polymorphisms have been investigated for possible associations with bipolar disorder (BD), but the results are controversial. Our goal was to investigate whether MAOA gene polymorphisms, especially the promoter uVNTR polymorphism and the EcoRV polymorphism, are associated either with BD or with different clinical subtypes of BD. A total of 714 Han Chinese subjects in Taiwan (305 controls and 409 BD patients) were recruited for study. All subjects were interviewed with the Chinese Version of the Modified Schedule of Affective Disorders and Schizophrenia-Lifetime; BD was diagnosed according to DSM-IV criteria. Genotyping for MAOA polymorphisms was performed using PCR and restriction fragment length polymorphism. The MAOA promoter polymorphisms uVNTR and EcoRV were not associated with BD or any of its subtypes, in either the frequencies of alleles or genotypes. In multiple logistic regression and haplotype frequency analysis, we confirmed these negative results in both females and males. Our results suggest that MAOA polymorphisms do not play a major role in pathogenesis of BD or its clinical subtypes in Han Chinese.

Norepinephrine transporter polymorphisms T-182C and G1287A are not associated with alcohol dependence and its clinical subgroups.

Several studies have suggested that the norepinephrine transporter (NET) may play an important role in the pathogenesis of alcohol dependence. Additional studies have shown that the polymorphisms of T-182C (rs2242446) and G1287A (rs5569) in NET gene (hSLC6A2) may affect the NET function. Therefore, in this study, we examined whether these hSLC6A2 gene polymorphisms are a susceptibility factor for alcohol dependence or its clinical subgroup(s). A total of 690 Han Chinese subjects (408 alcohol dependent patients and 282 controls) in Taiwan were recruited for this study. Individuals with alcohol dependence were classified into several clinical subgroups to reduce the clinical heterogeneity. All subjects were interviewed with identical methods, and the mental disorders were diagnosed according to DSM-IV criteria. The polymorphisms of T-182C and G1287A in hSLC6A2 gene were analyzed by using a standard method. No significant differences in genotype and allele frequencies of hSLC6A2 polymorphisms were found between controls and total alcohol dependence or between more homogeneous subgroups with alcohol dependence and controls. This study suggests that the polymorphisms of T-182C and G1287A in hSLC6A2 gene are not major risk factors in increasing susceptibility to either alcohol dependence or its clinical subtypes.

Lack of association between dopamine D3 receptor Ser9Gly polymorphism and schizophrenia in Han Chinese population.

BACKGROUND: The Ser9Gly polymorphism in dopamine D3 receptor gene (DRD3) was considered an important factor in the pathogenesis of schizophrenia. Allele and genotype frequencies of this polymorphism were studied in different ethnic groups of schizophrenic patients. However, the results have been inconclusive. OBJECTIVE: To determine whether the DRD3 Ser9Gly polymorphism is associated with schizophrenia or influences its psychopathological symptoms in Han Chinese population. METHOD: We recruited 256 schizophrenic patients and 285 normal controls matched for gender, age and ethnicity. Pretreatment psychotic symptoms were evaluated with the Positive and Negative Symptom Scale (PANSS) in 128 acutely exacerbated schizophrenic in-patients. Genotyping of Ser9Gly polymorphism was performed with a polymerase chain reaction restriction fragment length polymorphism method and reconfirmed by a direct sequencing technique. RESULTS: No significant difference was found between either patients with schizophrenia or with more homogeneous schizophrenic subgroups and healthy controls in genotype distributions and allele frequencies for the DRD3 Ser9Gly polymorphism. Similarly, DRD3 Ser9Gly genotype differences failed to reach significance in PANSS global, positive, negative and general symptoms scores. There is a trend (P = 0.064) towards higher PANSS positive symptoms scores in subjects carrying the Gly/Gly genotype. CONCLUSION: This study does not support the role of DRD3 Ser9Gly polymorphism in increasing genetic risk for schizophrenia in Han Chinese population. Still, there is a possibility that the DRD3 Ser9Gly variant may reflect genetic variation of severity of positive symptoms in acutely exacerbated schizophrenia. Further studies are warranted to investigate the effect of the DRD3 Ser9Gly polymorphism in relation to longer time course of schizophrenia, including treatment response to antipsychotics.