Family-based association studies of bipolar disorder with candidate genes involved in dopamine neurotransmission: DBH, DAT1, COMT, DRD2, DRD3 and DRD5

The dopaminergic system has been implicated in the aetiology of mood disorders. We conducted family-based association studies for polymorphisms at three genes involved in the metabolism of dopamine: dopamine transporter (DAT1), dopamine-beta-hydroxylase (DBH) and catechol-O-methyl transferase (COMT); and three dopamine receptors: DRD2, DRD3 and DRD5. We used a sample of 122 parent-offspring trios of British Caucasian origin where the proband had bipolar disorder I (BPI), and analysed the results with the transmission/disequilibrium test (TDT) which is robust to hidden population stratification. No statistically significant differences were found between transmitted and not transmitted alleles for any of the polymorphisms studied.     

Family association study between DRD2 and DRD3 gene polymorphisms and schizophrenia in a Portuguese population

Schizophrenia is a highly heritable condition, as demonstrated in family, twin and adoption studies. Candidate genes from the dopaminergic system have long been hypothesized to be involved in the etiology of this disorder. In the present study, we investigated the genetic association between polymorphisms in the D2 and D3 dopamine receptor (DRD2, DRD3) genes and schizophrenia. We examined 90 trios from Portugal, and negative results were obtained from association studies with both Haplotype Relative Risk (HRR) and Transmission Disequilibrium Test (TDT), as well as TRANSMIT. Therefore, we conclude that neither the DRD2 nor the DRD3 gene polymorphisms investigated are associated with schizophrenia in our sample.     

The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, starting in early childhood and persisting into adulthood in the majority of cases. Family and twin studies have demonstrated the importance of genetic factors and candidate gene association studies have identified several loci that exert small but significant effects on ADHD. To provide further clarification of reported associations and identify novel associated genes, we examined 1,038 single-nucleotide polymorphisms (SNPs) spanning 51 candidate genes involved in the regulation of neurotransmitter pathways, particularly dopamine, norepinephrine and serotonin pathways, in addition to circadian rhythm genes. Analysis used within family tests of association in a sample of 776 DSM-IV ADHD combined type cases ascertained for the International Multi-centre ADHD Gene project. We found nominal significance with one or more SNPs in 18 genes, including the two most replicated findings in the literature: DRD4 and DAT1. Gene-wide tests, adjusted for the number of SNPs analysed in each gene, identified associations with TPH2, ARRB2, SYP, DAT1, ADRB2, HES1, MAOA and PNMT. Further studies will be needed to confirm or refute the observed associations and their generalisability to other samples.     

No association between the DRD3 Ser9Gly polymorphism and schizophrenia

OBJECTIVE: To investigate the association between a Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) and schizophrenia. METHODS: 408 schizophrenic patients and 172 control subjects were compared with regard to their DRD3 Ser9Gly genotypic and allelic frequencies. In addition, we carried out a family-based association study including 183 pedigrees (472 subjects) using the transmission disequilibrium test (TDT). RESULTS: No significant differences of genotype or homozygosity distribution were identified between patients and controls. When patients were stratified according to gender, response to treatment, age at onset, no significant differences were observed. Neither allele A (Ser), or G (Gly) were preferentially transmitted from parents to affected offspring. CONCLUSION: The hypothesis that the DRD3 Ser9Gly polymorphism plays a predisposing role in schizophrenia is not supported by this study.     

DAT1 gene polymorphism in alcoholism: a family-based association study.

BACKGROUND: The present study tests the hypothesis that the 9-repeat allele of the dopamine transporter gene (DAT1; SLC6A3) is more frequent in alcohol-dependent probands--and in particular those with severe withdrawal symptoms (seizures and/or delirium)--compared to nonalcoholics. METHODS: To avoid stratification effects, the family-based association approach of Falk and Rubinstein was used in our sample of 87 alcohol-dependent probands and their biological parents. RESULTS: By applying a family-based association approach, we were not able to detect significant association between allele 9 at DAT1 (SLC6A3) and alcoholism as well as between patients with or without severe withdrawal symptoms. CONCLUSIONS: Based on our data, the impact of the 9-repeat allele of the dopamine transporter gene in alcoholism and the severity of alcohol withdrawal symptoms is putatively not substantial.     

DAT1和DRD4基因启动子区甲基化与注意缺陷多动障碍临床症状的关联研究

目的探索注意缺陷多动障碍(attention deficit hyperactivity disorder,ADHD)患儿多巴胺转运体基因(dopamine transporter gene,DAT1)、多巴胺D4受体基因(dopamine receptor D4 gene,DRD4)启动子区CpG岛甲基化状态与其临床症状严重程度的相关性。方法收集111例ADHD患儿精神类疾病家族史资料,并采用ADHD症状分级父母评定量表(attention deficit hyperactivity disorder rating scale-Ⅳhome version,ADHD-RS-Ⅳ)及自编对立违抗障碍(oppositional defiant disorder,ODD)量表对患者临床症状进行评定。采用亚硫酸氢钠测序法,检测患者外周血的DAT1、DRD4启动子区CpG岛目标片段甲基化状态。结果无抑郁、焦虑和ADHD家族史的患儿DAT1启动子区甲基化水平高于有抑郁、焦虑或ADHD家族史的患儿(P0.05)。DAT1和DRD4甲基化水平在ADHD-RS-Ⅳ总分(≤30分组与30分组)、注意缺陷因子分(≤17分组与17分组)、多动冲动因子分(≤13分组与13分组)低分和高分组的比较中差异均无统计学意义(均P0.05)。ODD量表9分的患儿DAT1甲基化水平较ODD量表得分≥9分的患儿高(P0.05),且患儿DAT1甲基化水平与ODD量表得分呈负相关(r=-2.203,P=0.033)。结论 DAT1启动子区甲基化水平可能影响ADHD患者对立违抗行为的严重程度,且与患者有无抑郁、焦虑和ADHD家族史存在一定关系。     

Association study of DRD3 gene in schizophrenia in Mexican sib-pairs

Schizophrenia is a heritable, complex mental disorder. We analysed the DRD3 gene as a candidate to be related to schizophrenia and clinical features in affected sib-pairs. A positive association with the -250A/Ser9 haplotype and a trend toward an association with formal thought disorder were observed. A synergic effect of DRD3 polymorphisms on schizophrenia susceptibility is suggested.     

Lack of association between VNTR polymorphism of DAT gene and schizophrenia

The substantial importance of genetic factors in the etiology of schizophrenia was demonstrated in many studies. The complex model of disease inheritance seems to be the most probable, involving epistatic interaction of many genes. Association studies are based on the analysis of the so-called candidate genes, which are coding for neurotransmitter receptors, neurotransmitter transporters and enzymes involved in their metabolism. In the present work the results of an association study of VNTR polymorphism of dopamine transporter gene (DAT) in schizophrenia are presented. This polymorphism is characterised by a different number of tandem repeats (VNTR) within the 3'-untranslated region of gene. In Caucasians the 40 base pair motif has 3 to 11 repeats, the most common (about 90%) are alleles containing 9 and 10 repeats. In the present study no association between the polymorphism studied and schizophrenia was found.     

DRD2 and ANKK1 genotype in alcohol-dependent patients with psychopathic traits: association and interaction study

BACKGROUND: The TaqI-A polymorphism of the ANKK1 gene, adjacent to the DRD2 gene, has been associated with alcoholism and other psychiatric conditions, although other DRD2 gene variants, such as the C957T polymorphism, could be related to these phenotypic traits. AIMS: To investigate the contribution of the TaqI-A and the C957T polymorphisms to the presence of psychopathic traits in patients with alcoholism. METHOD: We performed association and interaction analyses of the polymorphisms in 150 controls and 176 male alcohol-dependent patients assessed for the presence of dissocial personal disorder, using the Psychopathy Checklist-Revised (PCL-R). RESULTS: There was a significant association of the TaqI-A and C957T polymorphisms when both genotypes were present, with PCL-R scores of F(1-171=0.13) (P=0.01) and a frequency of dissocial personal disorder OR=10.52, P<0.001. CONCLUSIONS: The TaqI-A of the ANKK1 gene and the C957T of the DRD2 gene are epistatically associated with psychopathic traits in alcohol-dependent patients.     

Candidate system analysis in ADHD: Evaluation of nine genes involved in dopaminergic neurotransmission identifies association with DRD1

Abstract

Objectives. Several pharmacological and genetic studies support the involvement of the dopamine neurotransmitter system in the aetiology of attention-deficit hyperactivity disorder (ADHD). Based on this information we evaluated the contribution to ADHD of nine genes involved in dopaminergic neurotransmission (DRD1, DRD2, DRD3, DRD4, DRD5, DAT1, TH, DBH and COMT). Methods. We genotyped a total of 61 tagging single nucleotide polymorphisms (SNPs) in a sample of 533 ADHD patients (322 children and 211 adults), 533 sex-matched unrelated controls and additional 196 nuclear ADHD families from Spain. Results. The single- and multiple-marker analysis in both population and family-based approaches provided preliminary evidence for the contribution of DRD1 to combined-type ADHD in children (P = 8.8e-04; OR = 1.50 (1.18–1.90) and P = 0.0061; OR = 1.73 (1.23–2.45)) but not in adults. Subsequently, we tested positive results for replication in an independent sample of 353 German families with combined-type ADHD children and replicated the initial association between DRD1 and childhood ADHD (P = 8.4e-05; OR = 3.67 (2.04–6.63)). Conclusions: The replication of the association between DRD1 and ADHD in two European cohorts highlights the validity of our finding and supports the involvement of DRD1 in childhood ADHD.     

A family-based association study and gene expression analyses of netrin-G1 and -G2 genes in schizophrenia.

BACKGROUND: The netrin-G1 (NTNG1) and -G2 (NTNG2) genes, recently cloned from mouse, play a role in the formation and/or maintenance of glutamatergic neural circuitry. Accumulating evidence strongly suggests that disturbances of neuronal development and the N-methyl-d-aspartate receptor-mediated signaling system might represent a potential pathophysiology in schizophrenia. We therefore set out to examine the genetic contribution of human NTNG1 and NTNG2 to schizophrenia. METHODS: Twenty-one single nucleotide polymorphisms (SNPs) from NTNG1 and 10 SNPs from NTNG2 were analyzed in 124 schizophrenic pedigrees. All genotypes were determined with the TaqMan assay. The expression levels of NTNG1 and NTNG2 were examined in the frontal (Brodmann's Area [BA]11 and BA46) and temporal (BA22) cortices from schizophrenic and control postmortem brains. The isoform-specific expression of NTNG1 splice variants was assessed in these samples. RESULTS: Specific haplotypes encompassing alternatively spliced exons of NTNG1 were associated with schizophrenia, and concordantly, messenger ribonucleic acid isoform expression was significantly different between schizophrenic and control brains. An association between NTNG2 and schizophrenia was also observed with SNPs and haplotypes that clustered in the 5' region of the gene. CONCLUSIONS: The NTNG1 and NTNG2 genes might be relevant to the pathophysiology of schizophrenia.     

Examining impulsivity as an endophenotype using a behavioral approach: a DRD2 TaqI A and DRD4 48-bp VNTR association study

Background  

Research on the genetic basis for impulsivity has revealed an array of ambiguous findings. This may be a result of limitations to self-report assessments of impulsivity. Behavioral measures that assess more narrowly defined aspects of impulsivity may clarify genetic influences. This study examined the relationship between possession of the DRD2 TaqI A and DRD4 48 bp VNTR genetic polymorphisms and performance on a behavioral measure of impulsivity, the delay discounting task (DDT), and three traditional self-report measures.     

Mutation and association analysis of the 5' region of the dopamine D3 receptor gene in schizophrenia patients: identification of the Ala38Thr polymorphism and suggested association between DRD3 haplotypes and schizophrenia

Although the association between the Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) and schizophrenia has been investigated by many research groups, it is not known whether the Ser9Gly polymorphism alone or a variation in linkage disequilibrium may effect susceptibility to schizophrenia. We searched the 5' region of the DRD3 gene and found three novel polymorphisms: -712G/C, -205A/G, and Ala38Thr. The Ala38Thr polymorphism is located in the first transmembrane region and is conserved in the monkey, mouse, and rat. Case-control comparisons in 153 Japanese schizophrenia patients and 122 Japanese controls did not suggest an association between Ala38Thr and schizophrenia. However, there was a marginally significant association between the Ser9 allele of the Ser9Gly polymorphisms and schizophrenia (P = 0.02). Furthermore, there was a highly significant association between haplotypes of the -712G/C, -205A/G, and Ser9Gly polymorphisms and schizophrenia (P = 0.0007, corrected P = 0.007). These positive findings were replicated in an additional 99 Japanese schizophrenia patients and 132 controls (P = 0.04 and 0.0004, respectively). The most allelic differences of the Ser9Gly polymorphism between patient and control groups arose from the chromosome carrying specific alleles of the other three polymorphisms. This study indicates unknown variant(s) in linkage disequilibrium with the DRD3 haplotypes associated with schizophrenia.     

Extensive linkage disequilibrium mapping at HTR2A and DRD3 for schizophrenia susceptibility genes in the Galician population

The serotonin and dopamine neurotransmitter systems are candidate pathways in the development of schizophrenia because of the assumed causal relationship with the observed symptoms as well as effective targeting of the corresponding receptors by antipsychotic drugs. However, genetic association studies have systematically focused on a limited set of genes and single nucleotide polymorphisms (SNPs), including T102C at HTR2A and Ser9Gly at DRD3. Meta-analyses of the associations between these two markers and schizophrenia revealed a true increase in risk, the magnitude of the effect being very low. In the present study we analyzed 260 schizophrenic patients and 354 control subjects from a homogeneous population, the Galician population, using an extensive linkage disequilibrium (LD) mapping approach, genotyping a total of 47 SNPs to test for the existence of additional variants that confer higher risk. We detected nominal significant association with schizophrenia for several haplotype tag SNPs (htSNPs) at HTR2A, although the significance was lost after multiple test corrections. In addition, haplotype analyses involving a sliding window approach, with window size 2 to 4 SNPs, revealed significant differences in frequencies of the DRD3 haplotypes at the 3′ half of the gene region. This difference, which remains clearly significant after multiple test corrections (p = 0.002, 0.0001, and 0.0025, for window sizes 2, 3, and 4, respectively), was mainly due to over-representation of several rare haplotypes in patients, at the expense of a single common haplotype; this represents interesting evidence of rare haplotypes for susceptibility detected using common htSNPs due to their strong effect.     

多巴胺D2、D3受体基因多态性与汉族人精神分裂症相关研究

目的探索多巴胺D2受体(Dopamine D2receptor,DRD2)基因第8外显子Taq I A位点多态和多巴胺D3受体(Dopamine D3receptor,DRD3)基因第5内含子Msp I位点多态与汉族人群精神分裂症是否关联及其在不同性别是否存有差异。方法使用聚合酶链反应-限制性片段长度多态性(Polymerase chain reaction-re-striction fragment length polymorphism,PCR-RFLP)及DNA测序技术,对317例精神分裂症患者及310名对照DRD2Taq I A基因多态性和DRD3Msp I位点基因多态性进行检测。结果患者组与对照组间DRD2 Taq I A位点等位基因分布差异显著(P<0.01)、两两基因型对比(A1/A2与A1/A1相比:P<0.05;A2/A2与A1/A1相比:P<0.01)及两基因型联合对比(A1/A2+A2/A2与A1/A1:P<0.01)组间差异也显著。性别分层研究DRD2Taq I A位点女性组间差异显著(P<0.01),男性组间差异无意义(P>0.05)。DRD3Msp I位点的基因型频率、等位基因分布及性别分层分析等所有数据均显示患者组与对照组之间差异无统计学意义(P>0.05)。风险因子趋势检验结果DRD2Taq I A位点等位基因A2:P<0.01;DRD3Msp I位点等位基因2:P>0.05。结论所得数据支持DRD2Taq I A位点等位基因A2可能为精神分裂发生的风险因子,特别对女性而言。数据分析不支持DRD3Msp I位点基因与精神分裂发生有关。此结果需更进一步研究证实。     

No association between glutathione-synthesis-related genes and Japanese schizophrenia

Aims: 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. Methods: Seventeen single‐nucleotide polymorphisms (SNP) in GCLM, GCLC, and GSS were genotyped in 358 patients with schizophrenia and in 359 controls. Results: 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. Conclusions: The three primary GSH synthesis genes do not have an apparent degree of association with schizophrenia in the Japanese population.