Association between the DRD2 A1 allele and response to methadone and buprenorphine maintenance treatments.

The TaqI A polymorphism (A(1)) of the dopamine D(2) receptor gene (DRD2), although not a specific predictor of opioid dependence, has been strongly associated with high levels of prior heroin use and poor treatment outcomes among methadone maintenance patients. The aims of this study were to confirm these findings via a retrospective analysis of A(1) allele frequency in methadone (n = 46) and buprenorphine (n = 25) patients, and non-opioid-dependent controls (n = 95). Subjects were genotyped at the DRD2 TaqI A locus using PCR amplification followed by TaqI restriction enzyme digestion and gel electrophoresis. For methadone and buprenorphine subjects, heroin use (prior to treatment), treatment outcomes, and withdrawal occurrence were determined from comprehensive case notes. No significant differences in A(1) allele frequency (%) were observed between: methadone (19.6%), buprenorphine (18.0%), and control (17.9%) groups (P > 0.7); successful and poor treatment outcome groups, methadone: 20.0% and 19.2%, respectively (P = 1.0); buprenorphine: 18.4% and 20.0%, respectively (P = 1.0). Also, there were no significant relationships between TaqI A genotype and prior heroin use (P = 0.47). However, among the successful methadone subjects, significantly fewer A(1) allele carriers experienced withdrawal than non-A(1) carriers (P = 0.04). In conclusion, the DRD2 genotype effects did not affect opioid maintenance treatment outcomes. This suggests the need for a further prospective investigation into the role of the DRD2 A(1) allele in heroin use and response to maintenance pharmacotherapies for opioid dependence.     

Functional variant in the DRD2 receptor promoter region and subtypes of alcoholism

Dopaminergic pathway genes are considered as candidate genes for several neuropsychiatric diseases including severe alcoholism. Since 1990, there have been numerous reports of conflicting association studies of the Taq I A allele of the dopamine D2 receptor (DRD2) gene and alcoholism. Functional and structural variations in candidate genes offer more direct evaluation of their role in the development of a disorder. To determine the role of such variations in the DRD2 gene in the development of alcoholism subtypes, we screened a sample of 173 alcoholics and 88 normal controls with the A-241G and -141C Ins/Del variations in the promoter region and C311G variation in exon 7 of the DRD2 gene. Comparison of alcoholics with normal controls for allele frequency differences of these three variations was negative. Allele frequency differences of the two variations in the promoter region between type II alcoholics, alcoholics with medical complications, and normal controls were not significant. There was linkage disequilibrium only between -141 Ins/Del and Taq I D polymorphisms. We conclude that the functional and structural variations in DRD2 gene do not play a major role in the development of alcoholism subtypes in our sample.     

Hypothesizing dopaminergic genetic antecedents in schizophrenia and substance seeking behavior

The dopamine system has been implicated in both substance use disorder (SUD) and schizophrenia. A recent meta-analysis suggests that A1 allele of the DRD2 gene imposes genetic risk for SUD, especially alcoholism and has been implicated in Reward Deficiency Syndrome (RDS). We hypothesize that dopamine D2 receptor (DRD2) gene Taq1 A2 allele is associated with a subtype of non-SUD schizophrenics and as such may act as a putative protective agent against the development of addiction to alcohol or other drugs of abuse. Schizophrenics with SUD may be carriers of the DRD2 Taq1 A1 allele, and/or other RDS reward polymorphisms and have hypodopaminergic reward function. One plausible mechanism for alcohol seeking in schizophrenics with SUD, based on previous research, may be a deficiency of gamma type endorphins that has been linked to schizophrenic type psychosis. We also propose that alcohol seeking behavior in schizophrenics, may serve as a physiological self-healing process linked to the increased function of the gamma endorphins, thereby reducing abnormal dopaminergic activity at the nucleus accumbens (NAc). These hypotheses warrant further investigation and cautious interpretation. We, therefore, encourage research involving neuroimaging, genome wide association studies (GWAS), and epigenetic investigation into the relationship between neurogenetics and systems biology to unravel the role of dopamine in psychiatric illness and SUD.     

Allelic association analysis of the dopamine D2, D3, 5-HT2A, and GABA(A)gamma2 receptors and serotonin transporter genes with heroin abuse in Chinese subjects

Five candidate genes, the receptors DRD2, DRD3, HTR2A and GABA(A)gamma2, and the serotonin transporter (5-HTT) were analyzed for association with heroin abuse. We examined three polymorphisms (promoter - 141DeltaC, Ser311Cys, and TaqI) in the DRD2 gene, one polymorphism (Ser9Gly) in the DRD3 gene, two polymorphisms (promoter - 1438G/A and T102C) in the HTR2A gene, two polymorphisms (VNTR and Del/Ins) in 5-HTT gene, and one polymorphism (G3145A) in GABA(A)gamma2 gene in 121 Chinese heroin addicts and 194 controls. None of the polymorphisms differed significantly for allele, genotype, or haplotype frequencies, except for the DRD2 promoter polymorphism - 141DeltaC (genotype-wise and allele-wise, P = 0.05, uncorrected). An additional 344 subjects with heroin abuse and 104 controls were investigated for the - 141DeltaC polymorphism. In the second sample, there were no significant difference of genotype or allele frequencies between subjects with heroin abuse and normal controls. When we divided the sample by route of administration into nasal inhalers and IM or IV injectors, however, it produced a significant difference between inhalers of heroin and controls (genotype-wise, P = 0.006, allele-wise, P = 0.016) but not for injectors of heroin (genotype-wise, P = 0.81, allele-wise, P = 0.69). We also found that LD between all polymorphisms we examined in the gene was weak, possibly explaining why we see association of this polymorphism with heroin abuse but not with other markers in the gene. Overall our results indicates that the HTR2A, 5-HTT, DRD3 and GABA(A)gamma2 genes are not likely to be a major genetic risk factor for heroin abuse in this population, with the exception of possible association between nasal inhalation and DRD2 promoter - 141DeltaC polymorphism.     

Association between early-onset alcoholism and the dopamine D2 receptor gene

We examined the allelic association between the dopamine D2 receptor (DRD2) gene and alcoholism in 100 biologically unrelated Japanese alcoholics and 93 unrelated controls. Genomic DNA was prepared from peripheral white blood cells using the phenol-chloroform method. A 310-bp region surrounding the TaqA site at the DRD2 locus was amplified by polymerase chain reaction (PCR), and the PCR product was incubated with TaqI. The A1 allele remained intact while the A2 allele was cut. The frequency of the A1/A1 genotype and the frequency of the A1 allele were higher in early-onset alcoholics than in controls, P < 0.05 and P < 0.01, respectively. Moreover, the frequency of the A1/A1 genotype and the frequency of the A1 allele were higher in early-onset alcoholics with family histories of alcohol dependence than in controls, P < 0.01 and P < 0.01, respectively. The results indicate that the DRD2 gene is associated with susceptibility to early-onset alcoholism, and that each additional A1 allele shifts onset of alcoholism to an earlier age. Am. J. Med. Genet. 74:179–182, 1997. © 1997 Wiley-Liss, Inc.     

Allelic variations of the D2 dopamine receptor gene in children with idiopathic short stature

The D2 dopamine receptor (DRD2) plays a major role in growth hormone (GH) secretion. Recent reports indicate that Taq I A DRD2 gene alleles (A1 and A2) are related to the function of DRD2. Idiopathic short stature (ISS) is defined as short stature without accompanying malnutrition, chronic disease, and endocrinological disorders. However, some reports suggest that ISS is associated with a mild disturbance of GH secretion. In this study, we examined the notion that allelic variants of the DRD2 are associated with ISS. We studied 55 children with ISS aged 8.4 (SD 2.9) years; (group I) and 104 age-matched children of normal stature (group II). Informed consent was obtained from each child's parent or guardian. Genomic DNAs were extracted from peripheral mononuclear cells and amplified by polymerase chain reaction (PCR). The PCR products were digested by Taq1 and resolved by electrophoresis. The frequency of the A1 allele was significantly higher in group I (0.42) than in group II (0.26). The insulin-like growth factor (IGF)-I ratio (the ratio of the individual level to the normal mean value according to age at our laboratory center) was significantly lower in group I than in group II. When group I was subdivided into group A (with the A1 allele) and group B (with only the A2 allele), group A had a significantly lower peak GH response to the l-dopa test, lower levels of IGF-I, and retarded bone maturation. These findings indicate that polymorphism of the DRD2 gene may be one genetic factor that affects body height in childhood, acting through the hypothalamus (GH-releasing hormone) — pituitary (GH) — IGF-I axis. Received: July 13, 1998 / Accepted: September 9, 1998     

Potential association of DRD2 and DAT1 genetic variation with heroin dependence

The aim of our study was to investigate the potential association of dopamine receptor D2 gene (DRD2) TaqI RFLP A (rs1800497) and dopamine transporter gene (DAT) 3′untranslated region VNTR genetic variations with heroin addiction. Genotyping was performed using PCR-based techniques in 530 heroin abusers and 500 controls. Our results showed that DRD2 TaqI A1 allele carriers (genotypes A1A1 and A1A2) were prone to heroin abuse in models of dominance or co-dominance. We detected a 12 repeat allele and 6/6, 7/9, 9/11, 10/12 genotype in a Chinese/eastern Asian population for the first time. However, no significant differences in the DAT1 VNTR were found between the two groups in either genotypic or allelic distributions and there was no gene interaction between the two genetic loci.     

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.     

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 relationship between Taq1 a polymorphism of dopamine D(2) receptor gene and extrapyramidal adverse effects of selective dopamine D(2) antagonists, bromperidol, and nemonapride in schizophrenia: a preliminary study

The relationship between Taq1 A polymorphism of dopamine D(2) receptor (DRD(2)) gene and extrapyramidal adverse effects of bromperidol and nemonapride, which are both antipsychotic drugs with selective and potent DRD(2) antagonistic property, was investigated in Japanese schizophrenic inpatients. Twenty-seven patients were treated with bromperidol at 6 or 12 or 18 mg/day, while 25 patients were treated with nemonapride at 18 mg/day. The duration of treatment was 3 weeks. The A1 and A2 alleles were determined by PCR. The extrapyramidal adverse effects were assessed by the Udvalg for Kliniske Unders?ogelser side effects rating scale. Six patients were homozygous for the A1 allele, 27 were heterozygous for the A1 and A2 alleles, and 19 were homozygous for the A2 allele. There were no significant differences in the incidences or severity of extrapyramidal adverse effects between the patients with one or two A1 alleles and those with no A1 allele. The present study suggests that Taq1 A polymorphism is not related to the development of extrapyramidal adverse effects during acute phase of bromperidol and nemonapride treatments.     

A48G polymorphism in the D1 receptor genes associated with bipolar I disorder.

Several lines of evidence point to a role for dopamine in mood disorders and, in particular, in bipolar disorders. In line with a considerable amount of evidence, the dopamine D1 receptor gene (DRD1) is considered to be a good candidate gene for bipolar disorders. Several studies did not find any association between bipolar 1 patients and DRD1. In this study, we investigate a possible association between BP disorder and -48A/G polymorphism of the DRD1. We genotyped 107 bipolar 1 patients and 129 healthy control subjects of exclusively Sardinian descent. A statistically significant difference in genotype (chi2 = 6.29, df = 2, P = 0.042) and allele (chi2 = 5.46, df=1, P = 0.019; OR = 1.53, 95% CI = 1.08-2.16) frequencies was found, suggesting an association between the DRD1 gene and bipolar I disorder (BP I) in the Sardinian population.     

A dopamine D2 receptor gene-related polymorphism is associated with schizophrenia in a Spanish population isolate

Numerous lines of evidence have highlighted the involvement of the dopamine system in the pathophysiology of schizophrenia. Association studies of dopaminergic genes such as the dopamine D2 receptor gene (DRD2), however, have produced contradictory results. To test the hypothesis that DRD2 polymorphisms are associated with schizophrenia, we investigated two DRD2-related polymorphisms (TaqI A1/A2 or rs1800497 and -141-C Ins/Del or rs1799732) in a Spanish population isolate from northern Spain consisting of 165 controls and 119 patients with schizophrenia. The TaqI A1 allele was less frequent in schizophrenic patients than in controls (P=0.002). A similar association was found for the TaqI A2/A2 genotype (P=0.0003). No association was found for the DRD2 -141-C Ins/Del polymorphism. The strong association between a potentially functional polymorphism, downstream of the DRD2 gene and schizophrenia, suggests that the direct or indirect functional effects of this polymorphism, acting on either the ANKK1 or DRD2 genes, may play a role in the pathophysiology of schizophrenia.     

The interaction between BDNF and DRD2 in Bipolar II disorder but not in bipolar i disorder

Bipolar I (BP-I) and bipolar II (BP-II) disorders are the two most common subtypes of bipolar disorder. However, most studies have not differentiated bipolar disorder into BP-I and BP-II groups, for which the underlying etiology differentiating these two subtypes remains unclear. The genetic association between both subtypes is essential for improving our understanding. The dopamine D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1), one of the dopaminergic pathways, as well as the brain-derived neurotrophic factor (BDNF) gene, were reported as candidate genes in the etiology of bipolar disorder. Therefore, we examined the contribution of the BDNF and DRD2/ANKK1 genes and their interaction to the differentiation of BP-I and BP-II. Seven hundred ninety-two participants were recruited: 208 with BP-I, 329 with BP-II, and 255 healthy controls. The genotypes of the BDNF and DRD2/ANKK1 Taq1A polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. A significant main effect for the Val/Val genotype of the BDNF Val66Met polymorphism predicted BP-II patients. The significant interaction effect for the Val/Val genotype of the BDNF Val66Met polymorphism and A1/A2 genotype of DRD2/ANKK1 Taq1A polymorphism was found only in BP-II patients. We provide initial evidence that the BDNF Val66Me and DRD2/ANKK1 Taq1A polymorphisms interact only in BP-II disorder and that BP-I and BP-II are genetically distinct.     

Allelic association analysis of the dopamine D2, D3, 5‐HT2A,and GABAAγ2 receptors and serotonin transporter genes with heroin abuse in Chinese subjects

Five candidate genes, the receptors DRD2, DRD3, HTR2A and GABA_Aγ2, and the serotonin transporter (5‐HTT) were analyzed for association with heroin abuse. We examined three polymorphisms (promoter ? 141ΔC, Ser311Cys, and TaqI) in the DRD2 gene, one polymorphism (Ser9Gly) in the DRD3 gene, two polymorphisms (promoter ? 1438G/A and T102C) in the HTR2A gene, two polymorphisms (VNTR and Del/Ins) in 5‐HTT gene, and one polymorphism (G3145A) in GABA_Aγ2 gene in 121 Chinese heroin addicts and 194 controls. None of the polymorphisms differed significantly for allele, genotype, or haplotype frequencies, except for the DRD2 promoter polymorphism ? 141ΔC (genotype‐wise and allele‐wise, P = 0.05, uncorrected). An additional 344 subjects with heroin abuse and 104 controls were investigated for the ? 141ΔC polymorphism. In the second sample, there were no significant difference of genotype or allele frequencies between subjects with heroin abuse and normal controls. When we divided the sample by route of administration into nasal inhalers and IM or IV injectors, however, it produced a significant difference between inhalers of heroin and controls (genotype‐wise, P = 0.006, allele‐wise, P = 0.016) but not for injectors of heroin (genotype‐wise, P = 0.81, allele‐wise, P = 0.69). We also found that LD between all polymorphisms we examined in the gene was weak, possibly explaining why we see association of this polymorphism with heroin abuse but not with other markers in the gene. Overall our results indicates that the HTR2A, 5‐HTT, DRD3 and GABA_Aγ2 genes are not likely to be a major genetic risk factor for heroin abuse in this population, with the exception of possible association between nasal inhalation and DRD2 promoter ? 141ΔC polymorphism. © 2002 Wiley‐Liss, Inc.     

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.     

The D(2) dopamine receptor A(1) allele and opioid dependence: association with heroin use and response to methadone treatment

A total of 95 Caucasian opioid-dependent patients were followed over a one-year period in an outpatient methadone treatment program. The frequency of the TaqI A(1) allele of the D(2) dopamine receptor (DRD2) gene was 19.0% in these patients compared with 4.6% in controls free of past and current alcohol and other drug abuse and free of family history of alcohol and other drug abuse (p = 0.009). Twenty-two of these patients dropped out of the methadone program (Group A), 54 had a successful treatment (Group B), and 19 had a poor treatment (Group C) outcome. The frequency of the A(1) allele was highest in Group C (42.1%), followed by Group A (22.7%) and was lowest in Group B (9.3%). The more than fourfold higher frequency of the A(1) allele in the poor treatment outcome group compared with the successful treatment outcome group was significant (p = 0.00002). Moreover, the average use of heroin (grams/day) during the year prior to study entry was more than twice as great in patients with the A(1)(+) allele (A(1)/A(1) or A(1)/A(2) genotype) than those with the A(1)(-) allele (A(2)/A(2) genotype) (A(1)(+) allele = 0.55 +/- 0. 10, A(1)(-) allele = 0.25 +/- 0.05; p = 0.003). The results indicate that DRD2 variants are predictors of heroin use and subsequent methadone treatment outcome and suggest a pharmacogenetic approach to the treatment of opioid dependence.     

Relationship between Taq1 A dopamine D2 receptor (DRD2) polymorphism and prolactin response to bromperidol

The dopamine D2 receptor (DRD2) gene has a Taq1 A restriction fragment length polymorphism yielding two alleles, A1 and A2. We have previously shown that female patients with the A1 allele show greater prolactin response to nemonapride, a selective antagonist for D2-like dopamine receptors, in schizophrenic patients. In the present study, the relationship between this polymorphism and prolactin response to bromperidol was investigated in 32 untreated schizophrenic inpatients (16 males, 16 females). The daily dose of bromperidol was fixed at 6 (n = 10), 12 (n = 13), or 18 mg (n = 9) during a 2-week treatment period. Taq1 A genotypes were determined by PCR method. Plasma prolactin concentration was measured by radioimmunoassay. Plasma concentration of bromperidol was measured by HPLC method. The subjects were divided into four subgroups by gender and the genotypes, i.e., 10 males and 11 females with the A1 allele, 6 males and 5 females with no A1 allele. The females with the A1 allele had the highest Delta prolactin (the change from the pretreatment concentration)/bromperidol concentration ratio among the other groups (P < 0.05). The present study thus suggests that female patients with the A1 allele show greater prolactin response to bromperidol, who may have a high risk for adverse effects associated with neuroleptic-induced hyperprolactinemia.     

Association between the dopamine D3 receptor gene locus (DRD3) and unipolar affective disorder

Dopamine neurotransmission has been implicated in the pathophysiology of schizophrenia and, more recently, affective disorders. Among the dopamine receptors, D3 can be considered as particularly related to affective disorders due to its neuroanatomical localization in the limbic region of the brain and its relation to the serotoninergic activity of the CNS. The possible involvement of dopamine receptor D3 in unipolar (UP) major depression was investigated by a genetic association study of the D3 receptor gene locus (DRD3) on 36 UP patients and 38 ethnically matched controls. An allelic association of DRD3 (Bal I polymorphism) and UP illness was observed, with the Gly-9 allele (allele '2', 206/98 base-pairs long) being more frequent in patients than in controls (49% vs 29%, P < 0.02). The genotypes containing this allele (1-2 and 2-2) were found in 75% of patients vs 50% of controls (P < 0.03, odds ratio = 3.00, 95% CI = 1.12-8.05). The effect of the genotype remained significant (P < 0.02) after sex and family history were controlled by a multiple linear regression analysis. These results further support the hypothesis that dopaminergic mechanisms may be implicated in the pathogenesis of affective disorder. More specifically, the '2' allele of the dopamine receptor D3 gene seems to be associated with unipolar depression and can be considered as a 'phenotypic modifier' for major psychiatric disorders.     

Imaging gene–substance interactions: The effect of the DRD2 TaqIA polymorphism and the dopamine agonist bromocriptine on the brain activation during the anticipation of reward

Dopamine is known as the main neurotransmitter modulating the activation of the reward system of the brain. The DRD2 TaqIA polymorphism is associated with dopamine D2 receptor density which plays an important role in the context of reward. Persons carrying an A1 allele have a lower D2 receptor density and a higher risk to show substance abuse. The present study was designed to investigate the influence of the DRD2 TaqIA polymorphism and the selective D2 receptor agonist bromociptine on the activation of the reward system by means of functional magnetic resonance imaging (fMRI). In a double-blind crossover study with 24 participants we found an increase of reward system activation from placebo to bromocriptine only in subjects carrying the A1 allele. Furthermore, only A1 carrier showed an increase of performance under bromocriptine. The results are interpreted as reflecting a specific sensitivity for dopamine agonists in persons carrying an A1 allele and may complement actual data and theories of the development of addiction disorders postulating a higher genetic risk for substance abuse in carrier of the A1 allele.