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.     

Attention‐deficit hyperactivity disorder: A study of association with both the dopamine transporter gene and the dopamine D4 receptor gene

Attention‐deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders of childhood. The role of genetic factors in its etiology is strongly supported by family, adoption, and twin studies. Several investigations have reported associations between ADHD and both the 7‐repeat allele of the 48 bp VNTR at the DRD4 gene and the 10‐repeat allele of the 40 bp VNTR at the DAT1 gene, but the results have been inconsistent. A sample of 81 Brazilian ADHD children and adolescents and their parents were screened for these DRD4 and DAT1 VNTRs. An excess of the DRD4 7‐repeat allele was observed when both ADHD probands and their parents were compared with an ethnically matched control sample (chi‐square = 11.55, P = 0.03; chi‐square = 12.17, P = 0.03, respectively). However, haplotype relative risk (HRR) analysis showed no preferential transmission of the DRD4 7‐repeat allele. No evidence of association with the DAT1 polymorphism was detected by both approaches. Nevertheless, an interaction effect of both genes on ADHD hyperactive/impulsive dimension was observed (F = 4.68; P = 0.03). These results add to the group of studies that together suggest a small effect of these genes in the susceptibility to ADHD. © 2001 Wiley‐Liss, Inc.     

Dopamine receptor D3 gene and essential tremor in large series of German, Danish and French patients

The genetic causes of essential tremor (ET) seem to be heterogeneous. Recently, ET has been found associated with a functional variant (Ser9Gly) of the dopamine D₃ receptor (DRD3), located in the ETM1 locus on chromosome 3q13.3 described for the first time in 1997. We examined this variant in three different populations from Germany, Denmark and France. We undertook an association study of the Ser9Gly variant in 202 cases with a familial history from unrelated families with ET, 97 cases with isolated non-familial ET and 528 healthy controls. In addition, linkage and segregation analyses were carried out in 22 ET families. The distribution of genotypes and allele frequencies showed no significant differences in the whole sample and in a subanalysis of familial and sporadic cases. Age at onset of tremor, tremor duration and tremor severity did not show an association with the genotype. In addition, the DRD3 variant was not found linked to the disease in a subset of informative ET families. We did not find a significant association of the DRD3 variant with ET nor linkage to the DRD3 receptor in German, Danish and French ET patients and families, suggesting that it is unlikely to be a causal factor for ET.     

An association between a dopamine transporter gene (SLC6A3) haplotype and ADHD symptom measures in nonclinical adults

Previous genetic studies have postulated that attention deficit hyperactivity disorder (ADHD) should be regarded as the extreme end of a set of behavioural traits that can be continuously measured in the general population. The current study adopted a quantitative trait approach to examine the relationship between dopamine gene variants and self‐reported ADHD symptoms in 517 nonclinical adults. Although genetic associations with variants of both the dopamine transporter (DAT1; SLC6A3) and D4 receptor (DRD4) genes have been reliably reported in children, results in adults are less consistent. We probed two potentially functional variable number of tandem repeat (VNTR) polymorphisms in the 3′UTR and intron 8 of DAT1, the 10‐repeat and 6‐repeat alleles of which respectively form a haplotype (10/6 DAT1 haplotype) that is associated with childhood ADHD. We also genotyped the exon 3 VNTR of DRD4, the 7‐repeat allele of which is also an established risk factor for childhood ADHD. Permutation analysis showed an influence of the 10/6 DAT1 haplotype on both CAARS‐G and CAARS‐H (DSM‐IV ADHD Symptoms Total and ADHD Index respectively), such that ADHD symptom scores increased with each additional copy of the 10/6 DAT1 haplotype. This result survived corrections for multiple comparisons both at the level of genotype and phenotype. A nominal association with CAARS‐G was also found for the 7‐repeat allele of the DRD4 VNTR however this did not survive multiple comparison correction. Our results provide further support for the influence of variation in the 10/6 DAT1 haplotype and individual differences in ADHD symptoms in adults. © 2015 Wiley Periodicals, Inc.     

An Assessment of Transmission Disequilibrium Between Quantitative Measures of Childhood Problem Behaviors and DRD2/Taql and DRD4/48bp-Repeat Polymorphisms

In a pilot study of 120 children with reading disabilities, we assessed the presence of linkage and association between the DRD2/Taql and the DRD4/48bp-repeat polymorphisms and quantitative measures of behavioral problems derived from parental rated Child Behavior Checklist (CBCL) [Achenbach, T. M. (1991). TM Manual for the CBCL 14-18. Burlington, VT: University of Vermont]. Analyses included measures of between-family association, and a test of the presence of linkage and association by a logistic regression-based extension of the Transmission Disequilibrium Test (i.e., the logistic regression quantitative TDT). In between-family association analyses the "Social Problem" scale was weakly associated with the number of risk alleles of DRD2 and DRD4, while the "Withdrawn" scale was related to the number of risk alleles of DRD4 (the 7-repeat and the A1 allele respectively were considered the risk alleles). Logistic regression quantitative TDTs yielded statistically significant evidence in favor of linkage and association between DRD2 and "Social Problems" (Wald chi2 = 4.13, df = 1, p = 0.042, odds ratio = 1.97). A statistical trend in favor of linkage and association was found for "Withdrawn" and DRD4 (Wald chi2 = 2.65, df = 1, p = 0.104, odds ratio =1.44). Although preliminary, these findings are consistent with previous data that suggest a role of the same polymorphism in influencing individual sensitivity to reward and response to social cues and reinforcements in man and animal.     

No allelic association between Parkinson's disease and dopamine D2, D3, and D4 receptor gene polymorphisms

Parkinson's disease is thought to be caused by a combination of unknown environmental, genetic, and degenerative factors. Evidence from necropsy brain samples and pharmacokinetics suggests involvement of dopamine receptors in the pathogenesis or pathophysiology of Parkinson's disease. Genetic association studies between Parkinson's disease and dopamine D2, D3 and D4 receptor gene polymorphisms were conducted. The polymorphism was examined in 71 patients with Parkinson's disease and 90 controls. There were no significant differences between two groups in allele frequencies at the D2, D3, and D4 dopamine receptor loci. Our findings do not support the hypothesis that susceptibility to Parkinson's disease is associated with the dopamine receptor polymorphisms examined. © 1994 Wiley-Liss, Inc.     

Association of functional variants in the dopamine D2-like receptors with risk for gambling behaviour in healthy Caucasian subjects

Pathological gambling (PG) is an impulse control disorder with suggestive genetic vulnerability component. We evaluated the association of genetic variants in the dopaminergic receptor genes (DRD1-3s) with risk for gambling in healthy subjects using the Canadian Problem Gambling Index (CPGI). Healthy Caucasian subjects who had gambled at least once in their lifetime (n = 242) were included in the analysis. Gender was not associated with the CPGI, while younger age was associated with higher CPGI scores. We have found that none of the single polymorphisms investigated on DRD1 and DRD3 were associated with CPGI scores in healthy subjects. However, we observed trends for association on the TaqIA/rs1800497 polymorphism (P = 0.10) and the haplotype flanking DRD2 (G/C/A rs11604671/rs4938015/rs2303380; P = 0.06). Both trends were associated with lower CPGI score. Our results provide further evidence for the role of dopamine D2-like receptor in addiction susceptibility.     

Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1

The dopamine D2 receptor has been extensively studied in relation to alcoholism, substance abuse, and nicotine dependence. The most frequently examined polymorphism linked to this gene is the Taq1A restriction fragment length polymorphism (RFLP) (dbSNP rs1800497; g.32806C>T in GenBank AF050737.1), which has been associated with a reduction in D2 receptor density, although this is not universally accepted. The Taq1A RFLP lies 10 kB downstream of DRD2 and may therefore fall within a different coding region than the DRD2 gene or within a regulatory region. Within this downstream region, we have identified a novel kinase gene, named ankyrin repeat and kinase domain containing 1 (ANKK1), which contains a single serine/threonine kinase domain and is expressed at low levels in placenta and whole spinal cord RNA. This gene is a member of an extensive family of proteins involved in signal transduction pathways. The DRD2 Taq1A RFLP is a single nucleotide polymorphism (SNP) that causes an amino acid substitution within the 11th ankyrin repeat of ANKK1 (p.Glu713Lys), which, while unlikely to affect structural integrity, may affect substrate-binding specificity. If this is the case, then changes in ANKK1 activity may provide an alternative explanation for previously described associations between the DRD2 Taq1A RFLP and neuropsychiatric disorders such as addiction.     

No Association Between Polymorphisms in the Human Dopamine D3 and D4 Receptors Genes and Alcoholism

The human dopamine D₂ receptor gene (DRD₂) has received considerable attention for the past several years as a potential candidate that may affect susceptibility to alcoholism. The association studies that compared the frequencies of alleles of DRD₂ gene between alcoholics and control groups have produced equivocal results. Dopamine D₃ and D₄ receptor genes (DRD₃ and DRD₄) are in the same class as DRD₂ but with different pharmacological properties. We have used relative risk and haplotype relative risk approaches to test associations between alleles of DRD₃ and DRD₄ genes and alcoholism. For relative risk studies 162 probands from multiple incidence alcoholic families have been compared to 89 psychiatrically normal controls. Haplotype relative risk approaches have used 29 alcoholic probands in which both parents were available for genotyping. The Bal I restriction enzyme site in DRD₃ and tandem repeat (VNTR) in DRD₄ genes polymorphisms were used to genotype the above samples. The results of relative risk approaches for both DRD₃ and DRD₄ genes were negative for comparisons of alcoholics and subtypes of alcoholics with normal controls. Haplotype relative risk approaches also were negative for both genes. These results suggest that any role played by these receptors may account for only part of the variation in susceptibility to alcoholism. Am. J. Med. Genet. 74:281–285, 1997. © 1997 Wiley-Liss, Inc.     

DRD3 Ser9Gly and HS1BP3 Ala265Gly are not associated with Parkinson disease

Variants in the dopamine receptor D3 (DRD3) and HCLS1 binding protein 3 (HS1BP3) have been nominated as risk factors for essential tremor (ET). Although ET and Parkinson disease (PD) are considered different entities, they have many overlapping clinical and pathological features. We aim to evaluate the role of the Ser9Gly variant in DRD3 and Ala265Gly in HS1BP3 in PD development. To this end, we genotyped these two variants in a PD matched case–control series from the United States. Statistical analysis failed to identify significant differences in the frequency of these variants between the case and control groups; therefore our results do not support a role for these DRD3 and HS1BP3 variants in PD.     

Association of polymorphisms in the BDNF,DRD1 and DRD3 genes with tobacco smoking in schizophrenia

Emerging evidence indicates that the DRD1‐BDNF‐DRD3 cluster plays an important role in nicotine addiction. We have performed an association analysis of 42 SNPs within these genes with cigarette consumption in a group of 341 schizophrenia patients. The ACCG haplotype consisting of four BDNF markers (Val66Met (rs6265), rs11030104, rs2049045 and rs7103411) showed an association with the risk of smoking (p = 0.0002). Both DRD1 markers tested (rs4532 and rs686) and the DRD3 marker (rs1025398) showed association with quantity of tobacco smoked (p = 0.01, 0.005 and 0.002, respectively). Our findings are preliminary; however, they support the involvement of the DRD1, BDNF and DRD3 genes in smoking behaviour.     

Association between novelty-seeking and the dopamine D3 receptor gene in bipolar patients: A preliminary report

Recent studies in healthy controls suggest an association between novelty-seeking (NS) and the dopamine D4 receptor (DRD4) gene. In this study, we further investigated the relationship between genes implicated in dopamine as well as serotonin neurotransmission and personality traits in bipolar (BP) disorder. Scores on the Tridimensional Personality Questionnaire were examined in 37 recovered Research Diagnostic Criteria-diagnosed BP patients genotyped for DRD3, DRD4, and serotonin 2A receptor (5HTR2a) polymorphisms. Carriers of DRD3 allele 1 showed significantly lower NS values compared to patients without this allele. Scores on NS and on harm-avoidance were not related to DRD4 or 5HTR2a polymorphisms. These preliminary results suggest a role for D3 receptor in NS expression in BP patients. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:192–194, 1998. © 1998 Wiley-Liss, Inc.     

Overlapping Dopaminergic Pathway Genetic Susceptibility to Heroin and Cocaine Addictions in African Americans

Drugs of abuse activate the mesolimbic dopaminergic pathway. Genetic variations in the dopaminergic system may contribute to drug addiction. Several processes are shared between cocaine and heroin addictions but some neurobiological mechanisms may be specific. This study examined the association of 98 single nucleotide polymorphisms in 13 dopamine‐related genes with heroin addiction (OD) and/or cocaine addiction (CD) in a sample of 801 African Americans (315 subjects with OD ± CD, 279 subjects with CD, and 207 controls). Single‐marker analyses provided nominally significant evidence for associations of 24 SNPs) in DRD1, ANKK1/DRD2, DRD3, DRD5, DBH, DDC, COMT and CSNK1E. A DRD2 7‐SNPs haplotype that includes SNPs rs1075650 and rs2283265, which were shown to alter D2S/D2L splicing, was indicated in both addictions. The Met allele of the functional COMT Val158Met was associated with protection from OD. None of the signals remained significant after correction for multiple testing. The study results are in accordance with the results of previous studies, including our report of association of DRD1 SNP rs5326 with OD. The findings suggest the presence of an overlap in genetic susceptibility for OD and CD, as well as shared and distinct susceptibility for OD in subjects of African and European descent.     

Association and linkage studies of the TAQI A1 allele at the dopamine D2 receptor gene in samples of female and male alcoholics

To address the controversy surrounding DRD2 and alcoholism, we performed linkage and association studies utilizing alcoholic men from high-density families largely uncontaminated by other psychopathology and female alcoholics for whom secondary drug dependence (averaging 10 years later onset) was a prominent feature. The males and females were combined for a total of 52 alcoholics, and compared to 30 controls screened for the absence of alcoholism and other psychopathology, revealing a significant association between the frequency of the TaqI A1 allele and alcoholism. However, linkage and family-based association studies conducted on 20 families of male alcoholics found no evidence for association or linkage between Taq A and alcoholism. The results of our population-based association study, placed in the context of the literature, suggest that minimizing psychopathology in control groups is probably a more important explanation for divergent results than either sampling error or population stratification. When combined with the complete lack of within-family evidence, we conclude that the association, while not appearing to be artifactual, is not specific to the alcoholism phenotype, per se. © 1995 Wiley-Liss, Inc.     

Review of the putative association of dopamine D2 receptor and alcoholism: A meta-analysis

Eight recent studies have focused on the putative association of the dopamine D2 receptor (DRD2) gene and alcoholism. In this report, these studies are reviewed and the data and findings are examined in a meta-analysis. Four reports find a statistically significant increased risk for alcoholism in subjects carrying the A1 allele and 4 failed to observe a significant increase in risk. Overall, our metaanalysis of the results from all 8 studies supported a statistically significant association between the A1 allele of DRD2 and alcoholism, with an apparent increase in relative risk associated with increased severity of alcoholism. These results must be interpreted cautiously because the A1 allele of DRD2 varies significantly in frequency from one population to another. This variability in the population frequency of the A1 allele could result in an apparent association resulting from unrelated population differences. These findings support the need for carefully designed studies that minimize the ethnic heterogeneity of the subject and control populations. © 1993 Wiley-Liss, Inc.     

Adult attachment and gene polymorphisms of the dopamine D4 receptor and serotonin transporter (5-HTT)

Recently, the Dopamine D4 Receptor Gene (DRD4) and the Serotonin Transporter Gene (5-HTT) have been found to be candidate genes for infant attachment disorganization. The present study aimed to explore the relationship of these genes to adult attachment representations. The Adult Attachment Interview was used to assess attachment representations in 167 German adults. DNA from buccal cells was genotyped for the DRD4 VNTR Exon III and 5-HTT LPR polymorphisms with respect to the presence of the 7repeat allele and the short allele, respectively. DRD4 7repeat allele carriers were significantly more likely to be securely attached than those without 7repeat but only for subjects with unloving caregiver recollections. No association between the 5-HTT LPR polymorphism and adult attachment was found. These findings encourage further investigations to explore endophenotypical and mediating psychological processes between the DRD4 Gene and secure attachment patterns.     

Association study of dopamine D3 receptor gene and schizophrenia

Several groups have reported an association between schizophrenia and the MscI polymorphism in the first exon of the dopamine D3 receptor gene (DRD3). We studied this polymorphism using a North American sample (117 patients plus 188 controls) and an Italian sample (97 patients plus 64 controls). In the first part of the study, we compared allele frequencies of schizophrenia patients and unmatched controls and observed a significant difference in the total sample (P = 0.01). The second part of the study involved a case control approach in which each schizophrenia patient was matched to a control of the same sex, and of similar age and ethnic background. The DRD3 allele frequencies of patients and controls revealed no significant difference between the two groups in the Italian (N = 53) or the North American (N = 54) matched populations; however, when these two matched samples were combined, a significant difference was observed (P = 0.026). Our results suggest that the MscI polymorphism may be associated with schizophrenia in the populations studied. © 1995 Wiley-Liss, Inc.     

No association between a promoter dopamine D4 receptor gene variant and schizophrenia

The dopamine D₄ receptor has been implicated in the pathogenesis of schizophrenia. An association between a putative functional promoter polymorphism (?521C/T) in the dopamine D₄ receptor gene (DRD4) and schizophrenia was recently reported. In the present study, patients with schizophrenia (n = 132) and control subjects (n = 388) were analyzed with respect to the DRD4 ? 521C/T polymorphism. No significant case control differences emerged. The present results do not support a major role for DRD4 in the etiology of schizophrenia among Caucasians from Sweden. © 2001 Wiley‐Liss, Inc.