No association between the dopamine D3 receptor gene and Korean alcohol dependence

The genes encoding dopamine receptor (DR) subtypes have received considerable attention for the past several years as a potential candidate that may affect susceptibility to addictive disorder, including alcoholism. The many association studies that compared the frequencies of alleles of the dopamine D2 receptor (DRD2) gene between alcoholics and control groups have produced results, but some have been equivocal. Dopamine D3 receptor genes (DRD3) are in the same class as DRD2 but with different pharmacological properties. So we compared the distribution of genotypes and frequencies of BalI polymorphism of the DRD3 gene in alcoholics and controls to assess the role of the DRD3 gene in Korean alcoholism. For this study, 67 male probands from alcoholics and 67 age-matched normal male controls were engaged. No evidence for an allelic association was found between the A1 allele of DRD3 and alcoholism in a Korean population. These results suggest that any role played by this receptor may account for only part of the variation in susceptibility to alcoholism.     

传统抗精神病药物所致迟发性运动障碍的药理遗传学初步研究

目的：进一步探讨多巴胺D2、D3受体（dopamine D2,D3 receptor,DRD2,DRD3)功能基因多态性与迟发性运动障碍(tardive dyskinesia,TD）的相关性及各候选基因，同时包括五羟色胺2C受体（5－hydroxytryptamine 2C receptor,HTR2C）和锰超氧化物歧化酶（manganese superoxide dismutase,MnSOD）基因的相互作用对TD发生的影响。方法：使用异常不自主运动量表（abnormal involuntary movement scale,AIMS)评定精神分裂症（schizophrenia,CSH)患者有无TD及其严重程度，并采用简明精神病评定量表评定患者精神症状；应用聚合酶链反应－限制性片段长度多态性技术分析TD组和非TD组各候选基因等位基因和（或）基因型分布频率及其结合分布频率，并分析对AIMS总分值的影响。结果：各候选基因在SCH患者组以及TD和非TD组基因型分布均符合Hardy-Weinberg平衡定律；TD组HTR2C基因－697C（突变型）等位基因频率高于非TD组，差异有显著性（P＜0．05）；DRD2基因Taq I A1/A2、DRD3基因Ser9Gly和MnSOD基因Ala-9Val等位基因频率和基因型分布在TD组与非TD组之间差异均无显著性（P＞0．05）；仅DRD3突变型（Gly）和MnSOD野生型（Val）结合分布频率高于其它结合型，差异有显著性（P＜0．05）；但上述各候选基因不同等位基因和（或）基因型亚组间的临床学资料和AIMS总分值（TD值）差异均无显著性（P＞0．05）。结论：HTR2C基因启动区－697G→C单碱基置换可能是中国汉族男性SCH患者TD发生的易感因素；而SCH患者若同时携带DRD3基因9Gly突变型和MnSOD基因－9Val野生型等位基因可能增加了TD的易感性。     

No evidence for a major gene effect of the dopamine D4 receptor gene in the susceptibility to Gilles de la Tourette syndrome in five Canadian families

Gilles de la Tourette Syndrome (TS) is a neuropsychiatric disorder characterized by both motor and vocal tics affecting approximately 1/10,000 females and 1/2000 males. Because of the success of neuroleptics and other agents interacting with the dopaminergic system in the suppression of tics, a defect in the dopamine system has been hypothesized in the etiology of TS. In this paper we test the hypothesis that the dopamine D₄ receptor (DRD4) is linked to the genetic susceptibility to TS in five families. We tested three polymorphisms in the DRD4 gene and a polymorphism in the closely linked locus, tyrosine hydroxylase (TH). We found no evidence for linkage of DRD4 or TH to TS using an autosomal dominant model with reduced penetrance or using non-parametric methods. The presence of a mutation that results in a truncated non-functional D₄ receptor protein was also tested for, but was not observed in these families. © 1996 Wiley-Liss, Inc.     

Dopaminergic candidate genes in Tourette syndrome: association between tic severity and 3' UTR polymorphism of the dopamine transporter gene.

Multiple evidence suggests an involvement of the dopamine neurotransmitter system in Tourette syndrome (TS). Therefore, dopaminergic candidate genes are in the center of genetic association analyses of TS. In this study, 103 TS patients and their parents have been characterized for different dopamine-related polymorphisms including the 48 bp variable number of tandem repeats (VNTR) of the dopamine D4 receptor (DRD4) gene, the 40 bp VNTR of the dopamine transporter (DAT1, SLC6A3) gene and the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene. In addition, the 120 bp duplication and three single nucleotide polymorphisms (SNPs) were assessed in the promoter region of the DRD4 gene. The -616G allele and the 2-G-A-C haplotype (i.e., the 2-repeat form of the 120 bp sequence approximately -616G approximately -615A approximately -521C combination) were preferentially transmitted, however, these results did not remain significant after correction for multiple testing. Case-control analyses have also been carried out, resulting in negative findings. On the other hand, using a dimensional approach, the DAT1 40 bp VNTR showed an association with the peak tic-severity as measured by the Yale Global Tic Severity Scale. Patients with at least one copy of the 9-repeat allele had significantly more severe symptoms than individuals with the homozygous 10/10 genotype (P = 0.002). In summary, allele frequencies did not differ between cases and controls, but DAT1 genotype accounted for variations of tic severity within the TS group.     

Association study of dopamine D2 and D3 receptor gene polymorphisms with cocaine dependence

Genetic factors play a role in the vulnerability to cocaine dependence. The reinforcing properties of cocaine are related to the dopaminergic system, and, in particular, the dopamine receptors have been linked to the reward mechanisms. The present study examines the role of the variants TaqI A of the dopamine D2 receptor gene and BalI of the dopamine D3 receptor gene in a Brazilian sample consisting of 730 cocaine dependents and 782 healthy controls. The studied polymorphisms did not show any difference in allelic frequencies or genotypic distribution between the groups. Our data do not support a role for the dopamine D2 receptor gene TaqI A and dopamine D3 receptor gene BalI gene polymorphisms in the susceptibility to cocaine dependence in a Brazilian sample.     

Association analysis between polymorphisms in the dopamine D2 receptor (DRD2) and dopamine transporter (DAT1) genes with cocaine dependence

Genetic research on cocaine dependence (CD) may help clarify our understanding of the disorder as well as provide novel insights for effective treatment. Since dopamine neurotransmission has been shown to be involved in drug reward, related genes are plausible candidates for susceptibility to CD. The dopamine receptor D₂ (DRD2) protein and dopamine transporter (DAT1) protein play regulatory roles in dopamine neurotransmission. The TaqI A single-nucleotide polymorphism (SNP) in the DRD2 gene and the 3′ variable number tandem repeat (VNTR) polymorphism in the DAT1 gene have been implicated in psychiatric disorders and drug addictions. In this study, we hypothesize that these polymorphisms contribute to increased risk for CD. Cocaine-dependent individuals (n = 347) and unaffected controls (n = 257) of African descent were genotyped for the polymorphisms in the DRD2 and DAT1 genes. We observed no statistically significant differences or trends in allele or genotype frequencies between cases and controls for either of the tested polymorphisms. Our study suggests that there is no association between the DRD2 and DAT1 polymorphisms and CD. However, additional studies using larger sample sizes and clinically homogenous populations are necessary before confidently excluding these variants as contributing genetic risk factors for CD.     

DRD1基因4个多态性位点与注意缺陷多动障碍的关联分析

目的:探讨ADHD与DRD1基因4个多态性(G-48A,G-1251C,T-800C和T1403C)单个位点的关系.方法:对138名ADHD患者和119名正常对照进行以下遗传学分析:应用PCR-限制性内切酶分析技术分析4个SNP位点,检测各位点基因型和等位基因频率,经χ~2检验比较两组间各位点基因型及等位基因频率的差异.结果:①ADHD组中DRD1基因G-48A多态性-48C/-48G基因型频率明显低于对照组,差异有统计学意义(χ~2=4.318,P=0.045).②ADHD组和对照组在DRD1基因的其他3个多态性位点(G-1251C、T-800C和T1403C)等位基因和基因型频率分布均无统计学差异(P>0.05)).结论:①DRD1基因G-48A多态性与ADHD可能存在关联.-48G/-48G基因型可能是ADHD的保护因素.②DRD1基因的其他三个SNP(G-1251C,T800C和T1403C)与ADHD可能均无关联.     

广州地区汉族人群多巴胺受体基因多态性

目的 探讨广州地区汉族人群多巴胺Ｄ２（ＤＲＤ２）、Ｄ５（ＤＲＤ５）受体基因的多态性分布规律。方法 用聚合酶链反应－限制性片段长度多态性和聚合酶链反应－等位基因特异性扩增技术对１４１名广州地区汉族人的ＤＲＤ２、ＤＲＤ３、ＤＲＤ５基因多态性进行了检测,并与其他人群做了比较。结果 ＤＲＤ２基因３’端非翻译区的Ｔａｑ１Ａ突变点Ａ１（ＴａｑＩ－）、Ａ２（ＴａｑＩ＋）等位基因频率分别为４８％和５２％;Ａ１Ａ１     

Angiotensin I-converting enzyme ACE 2350*G and ACE-240*T-related genotypes and alleles are associated with higher susceptibility to endometriosis

Endometriosis displays features similar to malignancy, ranging from neovascularization to local invasion and aggressive spread to distant organs. The altered vascular-related genes might be related to the development of endometriosis. This study investigates whether angiotensin I-converting enzyme (ACE) *A2350G and A-240T gene polymorphisms could be used as markers of susceptibility in endometriosis. Women were divided into two groups: (1) endometriosis group (n=150) and (2) non-endometriosis group (n=159). Genomic DNA was obtained from peripheral leukocytes. ACE A2350G and A-240T gene polymorphisms were amplified by PCR and detected after restriction enzyme digestion with BstUI and XbaI. Genotypes and allelic frequencies in both groups were compared. We observed that genotype distribution and allele frequency of ACE 2350 and ACE-240 gene polymorphisms in both groups were significantly different. Proportions of ACE 2350*A homozygote/heterozygote/G homozygote in both groups were: (1) 66.7/29.3/4% and (2) 96.2/3.1/0.7%. Proportions of ACE-240*A homozygote/heterozygote/T homozygote in both groups were: (1) 43.3/46/10.7% and (2) 62.9/35.8/1.3%. We concluded that ACE 2350*G and ACE-240*T-related genotypes and alleles are associated with higher susceptibility to endometriosis. ACE A2350G and A-240T gene polymorphisms might be associated with endometriosis development.     

Lack of association between polymorphisms of the dopamine receptor D4 and dopamine transporter genes and personality traits in a Korean population

Human personality traits have a considerable genetic component. Cloninger et al. were the first to postulate that certain personality traits, such as novelty seeking, are related to the dopamine neurotransmitter system. In this study, we investigated the associations between dopamine receptor D4 (DRD4) exon III and dopamine transporter (DAT1) polymorphisms and personality traits. The DRD4 and DAT1 gene polymorphisms were genotyped in 214 healthy Korean subjects, whose personality traits were assessed with the Temperament and Character Inventory (TCI). There were no significant differences between scores of TCI temperament dimensions (novelty seeking, harm avoidance, reward dependence, and persistence) and DRD4 gene polymorphism. The DAT1 gene polymorphisms also showed no significant association with any of the temperament subscales of the TCI. These data suggest that DRD4 and DAT1 gene polymorphism may not associated with personality traits in a Korean population.     

Association study of 90 candidate gene polymorphisms in panic disorder

OBJECTIVE: In the present investigation we screened a large number of single nucleotide polymorphisms in the genes relevant to the neurobiology of anxiety for their association with panic disorder (PD). METHODS: The study sample included 127 patients with PD and 146 healthy control subjects. Using Arrayed Primer Extension technology we genotyped 90 polymorphisms in 21 candidate genes of serotonin, cholecystokinin, dopamine and opioid neurotransmitter systems. The association and haplotype analyses were performed in the whole group (PD-all) and in the subgroups of PD comorbid with major depression (PD-comorbid, n = 60) and without any comorbidity (PD-pure, n = 42). RESULTS: From the set of 90 polymorphisms, eight single nucleotide polymorphism markers in eight genes displayed at least a nominal association with any of the studied PD phenotype subgroups. Several polymorphisms of cholecystokinin, serotonin and dopamine systems were associated with PD-all and/or PD-comorbid phenotypes, while pure PD was associated only with HTR2A receptor 102T-C (P = 0.01) and DRD1 receptor -94G-A (P = 0.02) polymorphisms. Haplotype analysis supported an association of the cholecystokinin gene TG haplotype with the PD-all group (P = 0.04), whereas DRD1 receptor CAA and HTR2A receptor AT haplotypes were associated with a lower risk for PD-pure phenotype (P = 0.03 and P = 0.04, respectively). CONCLUSIONS: The study results suggest that genetic variants of several candidate genes of neurotransmitter systems, each of a minor individual effect, may contribute to the susceptibility to PD. Our data also indicate that genetic variability may have a distinctive influence on pure and comorbid phenotypes of PD.     

Association between three functional polymorphisms of dopamine D2 receptor gene and tardive dyskinesia in schizophrenia.

The dopamine D2 receptor (DRD2) gene is considered one of the candidate genes contributing to the development of tardive dyskinesia (TD). In the present study, we investigated the genetic association between three functional polymorphisms (Ser311Cys, -141C Ins/Del and TaqI A) in the DRD2 gene and TD (200 patients with schizophrenia: 44 with TD and 156 without TD). No significant difference in the allelic and genotypic distribution between patients with TD and those without TD was observed. However, we found a slightly significant association between the -141C Ins/Del polymorphism and the total Abnormal Involuntary Movement Scale (AIMS) score (P = 0.037). The significant association between the -141C Ins/Del polymorphism and the total AIMS score did not remain after the regression analysis was taken into account (P = 0.14). Our results suggest that that three functional polymorphisms in DRD2 may not play a major role in the occurrence of TD.     

Interleukin-1 gene complex in schizophrenia: an association study.

The aim of this study is to investigate the association between three polymorphisms of the interleukin-1 (IL-1) gene complex and schizophrenia. We genotyped 228 outpatients with schizophrenia (DSM-IV criteria) and 419 unrelated healthy controls. The following polymorphisms were analyzed: IL-1alpha -889 C/T, IL-1beta +3953 C/T, and IL-1RA (86 bp)n. No significant differences in genotype or in allelic distribution of the Il-1alpha, IL-1beta, and IL-1RA polymorphisms were found. Estimated haplotype frequencies were similar in both groups. Our data do not suggest that genetically determined changes in the IL-1 gene complex confer increased susceptibility for schizophrenia.     

Evaluation of potential gene-gene interactions for attention deficit hyperactivity disorder in the Han Chinese population.

Several lines of evidence suggest that attention-deficit/hyperactivity disorder (ADHD) is a polygenic disorder produced by the interaction of several genes with minor effects. To explore potential gene-gene interactions among candidate genes for ADHD, we studied the dopamine D2 receptor (DRD2), dopamine D4 receptor (DRD4), dopamine transporter (DAT1), and catechol-O-methyltransferase (COMT) genes in the Han Chinese population. A sample of 340 children with ADHD was diagnosed according to the DSM-IV criteria. We also recruited 226 unrelated controls. Identified polymorphisms included a 48-base-pair-repeat in Exon 3 of DRD4, a 40-base-pair-repeat in the 3' untranslated region of DAT1, a restriction-fragment-length polymorphism at codon 158 of COMT, and a -241A > G transition in the promoter of DRD2. Associations of polymorphisms with ADHD and its subtypes were examined by comparing allele frequencies between probands and controls. Binary logistic regression analysis was used to examine the potential gene-gene interactions. Binary logistic regression analysis with the sample of refined phenotypes showed that male gender and long-repeat genotypes of DRD4 and DAT1 were independent risk factors for ADHD. We found no evidence for gene-gene interactions among the candidate genes studied. The present study suggests that dopamine candidate genes are associated with increased vulnerability to ADHD in the Han Chinese population.     

Meta-analysis of DRD3 gene and schizophrenia: Ethnic heterogeneity and significant association in caucasians

The involvement of dopamine in the etiology of schizophrenia is suggested by a number of neurobiological and pharmacological data, the dopamine D3 receptor (DRD3) being selectively expressed in brain regions which may be specifically involved in the risk for schizophrenia. The gene coding for DRD3 has thus been extensively analyzed. Since the initial report providing substantial evidence for an association of homozygosity of either allele of the gene coding for DRD3 (BalI polymorphisms) with schizophrenia, a flurry of replicating studies has appeared, which have been split into confirmations and nonreplications in North European Caucasian, Mediterranean, Asian, American, and African populations. The involvement of DRD3 polymorphisms thus remains questionable, particularly as no linkage studies have favored a nonrandom segregation of DRD3 alleles and schizophrenia. We performed a metaanalysis from 29 independent samples, from 24 different association studies so far published, allowing the examination of 2,619 schizophrenic patients and 2,517 controls. No significant differences of genotype counts were noted between patients and controls for the whole sample, considering frequency of any genotype. Starting from the high variability of the genotypes in different geographical areas, the impact of ethnic heterogeneity was taken into account. When the studies were reorganized in five groups according to geographical origin of samples, both homozygosity and 1-1 genotype revealed significant heterogeneity (P < 0.05). We specifically found an excess of homozygosity and 1-1 genotype in schizophrenic patients only in the African and Caucasian groups (P < 0.05). The present analysis suggests a small but significant effect of DRD3 in the susceptibility to schizophrenia, at least in Caucasians. Am. J. Med. Genet. (Neuropyschiatr. Genet.) 81:318–322, 1998. © 1998 Wiley-Liss, Inc.     

Association testing of panic disorder candidate genes using CCK-4 challenge in healthy volunteers

Despite continuing efforts to determine genetic vulnerability to panic disorder (PD), the studies of candidate genes in this disorder have produced inconsistent or negative, results. Laboratory panic induction may have a potential in testing genetic substrate of PD. In this study we aimed to explore the effects of several genetic polymorphisms previously implicated in PD on the susceptibility to cholecystokinin-tetrapeptide (CCK-4) challenge in healthy subjects. The study sample consisted of 110 healthy volunteers (47 males and 63 females, mean age 22.2 +/- 5.2) who participated in CCK-4 challenge test. Nine gene-candidates, including 5-HTTLPR, MAO-A VNTR, TPH2 rs1386494, 5-HTR1A -1019C-G, 5-HTR2A 102T-C, CCKR1 246G-A, CCKR2 -215C-A, DRD1 -94G-A and COMT Val158Met, were selected for genotyping based on previous positive findings from genetic association studies in PD. After CCK-4 challenge, 39 (35.5%) subjects experienced a panic attack, while 71 subjects were defined as non-panickers. We detected significant differences for both genotypic and allelic frequencies of 1386494A/G polymorphism in TPH2 gene between panic and non-panic groups with the frequencies of G/G genotype and G allele significantly higher in panickers. None of the other candidate loci were significantly associated with CCK-4-induced panic attacks in healthy subjects. In line with our previous association study in patients with PD, we detected a possible association between TPH2 rs1386494 polymorphism and susceptibility to panic attacks. Other polymorphisms previously associated with PD were unrelated to CCK-4-induced panic attacks, probably due to the differences between complex nature of PD and laboratory panic model.     

Lack of association between TaqI A1 allele of dopamine D2 receptor gene and alcohol-use disorders in Atayal natives of Taiwan

Association studies between the A1 allele of the dopamine D2 receptor (DRD2) gene TaqI A polymorphism and alcoholism remain controversial. A recent study from Japan demonstrated that the A1 allele is associated with severe alcoholism in the Japanese population. We were interested in knowing if this association also exists in the Atayals of Taiwan, who were found to have a higher prevalence of alcohol-use disorders than the Han Chinese in Taiwan. Genotype and allele frequencies were determined in alcohol-abusing, alcohol-dependent, and nonalcoholic control Atayal natives in Taiwan. A1 allele frequencies in alcohol-dependent, alcohol-abusing, and normal control Atayals were 0.39, 0.42, and 0.39, respectively. No difference in A1 allele frequency was found among these three groups. Our data do not support the hypothesis that the A1 allele of the TaqI A polymorphism of the DRD2 gene increases susceptibility to alcohol-use disorders in the Atayals of Taiwan. © 1996 Wiley-Liss, Inc.     

Dopamine D4 receptor variants in chinese sporadic and familial schizophrenics

Variation in the number of tandem repeats of a 48 base pair (bp) unit was found in the gene of the dopamine D4 receptor (DRD4). The number of repetitions of the 48bp unit was shown to influence the binding of clozapine, which suggests that different alleles may function differently in vivo and affect the pathogenesis of schizophrenia. Genotypes of DRD4 polymorphism were analyzed for 47 schizophrenic probands who had at least one living sibling with a diagnosis of schizophrenia, 35 unaffected siblings of the schizophrenic proband, 42 sporadic schizophrenic patients, and 43 healthy controls without a family history of psychosis. There was no significant difference in genotypic or allelic distributions among the four groups. Significant differences in the frequencies of two- and seven-repeats alleles between the Chinese and Caucasians controls were noted. The present study did not support that a particular allele or genotype of the 48bp-repeat of DRD4 was associated with schizophrenia. Am. J. Med. Genet. 74:412–415, 1997. © 1997 Wiley-Liss, Inc.     

Mutation screening of the dopamine D2 receptor gene in attention-deficit hyperactivity disorder subtypes: preliminary report of a research strategy

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable syndrome with onset in childhood that is associated with clinical response to drugs, which increase the release of monoamines, especially dopamine. A variety of studies have reported on genetic associations of ADHD with polymorphisms for various component genes of the dopamine pathway. The promise of preliminary associations found with several genes is mitigated by the significant controversy that exists over what are the appropriate clinical characteristics of ADHD associated with its familial transmission. In the current report, we describe a strategy for mutation screening in common, complex disorders and its application to the systematic screening for coding region variation in the dopamine D2 receptor (DRD2) gene. We used groups of individuals who met diagnostic criteria for DSM-IV-defined ADHD subtypes, as well as recently defined latent class criteria for pure familial forms of ADHD. No coding region sequence variations were identified in the DRD2 gene that met our requirements for prevalence to be considered a candidate variant contributing to susceptibility for ADHD.