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1.  Multivariate Analysis of Dopaminergic Gene Variants as Risk Factors of Heroin Dependence 
PLoS ONE  2013;8(6):e66592.
Heroin dependence is a debilitating psychiatric disorder with complex inheritance. Since the dopaminergic system has a key role in rewarding mechanism of the brain, which is directly or indirectly targeted by most drugs of abuse, we focus on the effects and interactions among dopaminergic gene variants.
To study the potential association between allelic variants of dopamine D2 receptor (DRD2), ANKK1 (ankyrin repeat and kinase domain containing 1), dopamine D4 receptor (DRD4), catechol-O-methyl transferase (COMT) and dopamine transporter (SLC6A3) genes and heroin dependence in Hungarian patients.
303 heroin dependent subjects and 555 healthy controls were genotyped for 7 single nucleotide polymorphisms (SNPs) rs4680 of the COMT gene; rs1079597 and rs1800498 of the DRD2 gene; rs1800497 of the ANKK1 gene; rs1800955, rs936462 and rs747302 of the DRD4 gene. Four variable number of tandem repeats (VNTRs) were also genotyped: 120 bp duplication and 48 bp VNTR in exon 3 of DRD4 and 40 bp VNTR and intron 8 VNTR of SLC6A3. We also perform a multivariate analysis of associations using Bayesian networks in Bayesian multilevel analysis (BN-BMLA).
Findings and conclusions
In single marker analysis the TaqIA (rs1800497) and TaqIB (rs1079597) variants were associated with heroin dependence. Moreover, –521 C/T SNP (rs1800955) of the DRD4 gene showed nominal association with a possible protective effect of the C allele. After applying the Bonferroni correction TaqIB was still significant suggesting that the minor (A) allele of the TaqIB SNP is a risk component in the genetic background of heroin dependence. The findings of the additional multiple marker analysis are consistent with the results of the single marker analysis, but this method was able to reveal an indirect effect of a promoter polymorphism (rs936462) of the DRD4 gene and this effect is mediated through the –521 C/T (rs1800955) polymorphism in the promoter.
PMCID: PMC3696122  PMID: 23840506
2.  Genetic influence of dopamine receptor, dopamine transporter, and nicotine metabolism on smoking cessation and nicotine dependence in a Japanese population 
BMC Genetics  2014;15:151.
This study investigated whether polymorphisms of the ankyrin repeat and kinase domain containing 1 gene (ANKK1), which is adjacent to the dopamine D2 receptor gene (DRD2), and the dopamine transporter (SLC6A3) and cytochrome P450 2A6 (CYP2A6) genes influence smoking cessation and nicotine dependence in a Japanese population. In 96 current and former smokers, genotyping frequencies for the ANKK1/DRD2 TaqIA, SLC6A3 VNTR, and CYP2A6 polymorphisms were subjected to chi-square analysis, and regression analyses were used to determine the association of the genotypes of current smokers with a Heavy Smoking Index, in addition to evaluating the effect of the subjects’ smoking history on the association.
Genotyping results suggested that nicotine dependence among current smokers homozygous for the SLC6A3 10r allele was lower than that of smokers carrying the minor alleles, and that the CYP2A6 polymorphism might mediate this association. Furthermore, the age at which current smokers began smoking might moderate the association between their genetic polymorphisms and nicotine dependence.
This study provides preliminary findings on the influence of genetic variants on the smoking phenotypes in a Japanese population.
PMCID: PMC4307219  PMID: 25526961
ANKK1/DRD2 TaqIA polymorphism; CYP2A6*4 polymorphism; Nicotine dependence SLC6A3 VNTR polymorphism; Smoking cessation
Behavioural pharmacology  2008;19(5-6):641-649.
Negative mood increases smoking reinforcement and risk of relapse. We explored associations of gene variants in the dopamine, opioid, and serotonin pathways with smoking reward (“liking”) and reinforcement (latency to first puff, total puffs) as a function of negative mood and expected vs. actual nicotine content of the cigarette. Smokers of European ancestry (n=72) were randomized to one of four groups in a 2 × 2 balanced-placebo design, corresponding to manipulation of actual (0.6 mg vs. 0.05 mg) and expected (told nicotine, told denicotinized) nicotine “dose” in cigarettes during each of two sessions (negative vs. positive mood induction). Following mood induction and expectancy instructions, they sampled and rated the assigned cigarette, and then smoked additional cigarettes ad lib during continued mood induction. The increase in smoking amount due to negative mood was associated with: DRD2 C957T (CC>TT or CT), SLC6A3 (presence of 9 repeat > absence of 9), and among those given a nicotine cigarette, DRD4 (presence of 7 repeat > absence of 7) and DRD2/ANKK1 TaqIA (TT or CT > CC). SLC6A3 and DRD2/ANKK1 TaqIA were also associated with smoking reward and smoking latency. OPRM1 (AA > AG or GG) was associated with smoking reward, but SLC6A4 VNTR was unrelated to any of these measures. These results warrant replication but provide the first evidence for genetic associations with the acute increase in smoking reward and reinforcement due to negative mood.
PMCID: PMC2717609  PMID: 18690118
smoking reward; reinforcement; mood; genetics; dopamine
4.  Effects of Nicotine Deprivation and Replacement on BOLD-fMRI Response to Smoking Cues as a Function of DRD4 VNTR Genotype 
Nicotine & Tobacco Research  2014;16(7):939-947.
Reactivity to smoking cues is an important factor in the motivation to smoke and has been associated with the dopamine receptor 4 variable number tandem repeat (DRD4 exon III VNTR) polymorphism. However, little is known about the associated neural mechanisms.
Non-treatment-seeking Caucasian smokers completed overnight abstinence and viewed smoking and neutral cues during 2 separate functional magnetic resonance imaging scans while wearing either a nicotine or placebo patch (order randomized) and were genotyped for the DRD4 VNTR. We conducted mixed-effects repeated-measures analyses of variance (within-subject factor: nicotine or placebo patch; between-subject factor: DRD4 long [L: ≥1 copy of ≥7 repeats] or short [S: 2 copies ≤6 repeats] genotype) of 6 a priori regions of interest.
Relative to neutral cues, smoking cues elicited greater activity in bilateral ventral striatum and left amygdala during nicotine replacement and deactivation in these regions during nicotine deprivation. A patch × DRD4 interaction was observed in the left amygdala, an area associated with appetitive reinforcement and relapse risk, such that S allele carriers demonstrated greater activation on active patch than on placebo patch.
Brain systems associated with reward salience may become primed and overreactive at nicotine replacement doses intended for the first step of smoking cessation and may become inhibited during nicotine withdrawal in DRD4 S but not in DRD4 L carriers. These findings are consistent with the role of these regions in drug reinforcement and suggest a differential influence of nicotine replacement on amygdala activation in the association of incentive salience with smoking stimuli across DRD4 genotypes.
PMCID: PMC4072897  PMID: 24659022
5.  ‘Smoking Genes’: A Genetic Association Study 
PLoS ONE  2011;6(10):e26668.
Some controversy exists on the specific genetic variants that are associated with nicotine dependence and smoking-related phenotypes. The purpose of this study was to analyse the association of smoking status and smoking-related phenotypes (included nicotine dependence) with 17 candidate genetic variants: CYP2A6*1×2, CYP2A6*2 (1799T>A) [rs1801272], CYP2A6*9 (−48T>G) [rs28399433], CYP2A6*12, CYP2A13*2 (3375C>T) [rs8192789], CYP2A13*3 (7520C>G), CYP2A13*4 (579G>A), CYP2A13*7 (578C>T) [rs72552266], CYP2B6*4 (785A>G), CYP2B6*9 (516G>T), CHRNA3 546C>T [rs578776], CHRNA5 1192G>A [rs16969968], CNR1 3764C>G [rs6928499], DRD2-ANKK1 2137G>A (Taq1A) [rs1800497], 5HTT LPR, HTR2A −1438A>G [rs6311] and OPRM1 118A>G [rs1799971]. We studied the genotypes of the aforementioned polymorphisms in a cohort of Spanish smokers (cases, N = 126) and ethnically matched never smokers (controls, N = 80). The results showed significant between-group differences for CYP2A6*2 and CYP2A6*12 (both P<0.001). Compared with carriers of variant alleles, the odds ratio (OR) for being a non-smoker in individuals with the wild-type genotype of CYP2A6*12 and DRD2-ANKK1 2137G>A (Taq1A) polymorphisms was 3.60 (95%CI: 1.75, 7.44) and 2.63 (95%CI: 1.41, 4.89) respectively. Compared with the wild-type genotype, the OR for being a non-smoker in carriers of the minor CYP2A6*2 allele was 1.80 (95%CI: 1.24, 2.65). We found a significant genotype effect (all P≤0.017) for the following smoking-related phenotypes: (i) cigarettes smoked per day and CYP2A13*3; (ii) pack years smoked and CYP2A6*2, CYP2A6*1×2, CYP2A13*7, CYP2B6*4 and DRD2-ANKK1 2137G>A (Taq1A); (iii) nicotine dependence (assessed with the Fagestrom test) and CYP2A6*9. Overall, our results suggest that genetic variants potentially involved in nicotine metabolization (mainly, CYP2A6 polymorphisms) are those showing the strongest association with smoking-related phenotypes, as opposed to genetic variants influencing the brain effects of nicotine, e.g., through nicotinic acetylcholine (CHRNA5), serotoninergic (HTR2A), opioid (OPRM1) or cannabinoid receptors (CNR1).
PMCID: PMC3202555  PMID: 22046326
6.  Association between DRD2/ANKK1 TaqIA Polymorphism and Susceptibility with Tourette Syndrome: A Meta-Analysis 
PLoS ONE  2015;10(6):e0131060.
Genetic factors are important in the pathogenesis of Tourette syndrome (TS). Notably, Dopamine receptor D2 (DRD2) gene has been suggested as a possible candidate gene for this disorder. Several studies have demonstrated that DRD2/ANKK1 TaqIA polymorphism is associated with an increased risk of developing TS. However, past results remain conflicting. We addressed this controversy by performing a meta-analysis of the relationship between DRD2/ANKK1 TaqIA polymorphism and TS.
Literature was searched in multiple databases including PUBMED, COCHRANE and WEB OF SCIENCE up to July 2014. The number of the genotypes for DRD2/ANKK1 TaqIA in the TS and control subjects was extracted and statistical analysis was performed using Review Manager 5.0.16 and Stata 12.0 software. Summary odds ratios (ORs) and 95% confidence intervals (95%CIs) were utilized to calculate the risk of TS with DRD2/ANKK1 TaqIA. Stratified analysis based on ethnicity was also conducted.
523 patients with TS, 564 controls and 87 probands plus 152 relatives from five published studies were finally involved in this meta-analysis. Combined analysis revealed that the overall ORs for the DRD2/ANKK1 TaqIA A1 allele were 1.69 (95%CIs = 1.42-2.00) in the fixed-effect model and 1.66 (95%CIs = 1.33-2.08) in the random-effects model. Stratification by ethnicity indicated the TaqIA A1 allele was significantly associated with TS in Caucasians (fixed-effect model: OR=1.75, 95%CI = 1.43-2.16; random-effect model: OR=1.69, 95%CI = 1.25-2.28) and in Asians (OR=1.54, 95%CI = 1.12-2.10). Meta-analysis of the A1A1 vs. A2A2 (homozygous model), A1A2 vs. A2A2 (heterozygous model) and A1A1+A1A2 vs. A2A2 (dominant model) of this polymorphism revealed a significant association with TS in overall populations and Caucasians.
This meta-analysis suggested that the DRD2/ANKK1 TaqIA polymorphism might contribute to TS susceptibility, especially in Caucasian population. However, further investigation with a larger number of worldwide studies should be conducted to verify the association.
PMCID: PMC4482493  PMID: 26110876
7.  Association between dopaminergic polymorphisms and borderline personality traits among at-risk young adults and psychiatric inpatients 
In the development of borderline personality disorder (BPD) both genetic and environmental factors have important roles. The characteristic affective disturbance and impulsive aggression are linked to imbalances in the central serotonin system, and most of the genetic association studies focused on serotonergic candidate genes. However, the efficacy of dopamine D2 receptor (DRD2) blocking antipsychotic drugs in BPD treatment also suggests involvement of the dopamine system in the neurobiology of BPD.
In the present study we tested the dopamine dysfunction hypothesis of impulsive self- and other-damaging behaviors: borderline and antisocial traits were assessed by Structured Clinical Interview for Diagnosis (SCID) for DSM-IV in a community-based US sample of 99 young adults from low-to-moderate income families. For the BPD trait analyses a second, independent group was used consisting of 136 Hungarian patients with bipolar or major depressive disorder filling out self-report SCID-II Screen questionnaire. In the genetic association analyses the previously indicated polymorphisms of the catechol-O-methyl-transferase (COMT Val158Met) and dopamine transporter (DAT1 40 bp VNTR) were studied. In addition, candidate polymorphisms of the DRD2 and DRD4 dopamine receptor genes were selected from the impulsive behavior literature.
The DRD2 TaqI B1-allele and A1-allele were associated with borderline traits in the young adult sample (p = 0.001, and p = 0.005, respectively). Also, the DRD4 -616 CC genotype appeared as a risk factor (p = 0.02). With severity of abuse accounted for in the model, genetic effects of the DRD2 and DRD4 polymorphisms were still significant (DRD2 TaqIB: p = 0.001, DRD2 TaqIA: p = 0.008, DRD4 -616 C/G: p = 0.002). Only the DRD4 promoter finding was replicated in the independent sample of psychiatric inpatients (p = 0.007). No association was found with the COMT and DAT1 polymorphisms.
Our results of the two independent samples suggest a possible involvement of the DRD4 -616 C/G promoter variant in the development of BPD traits. In addition, an association of the DRD2 genetic polymorphisms with impulsive self-damaging behaviors was also demonstrated.
PMCID: PMC2823641  PMID: 20205808
Drug and alcohol dependence  2008;99(1-3):47-57.
Initial sensitivity to nicotine’s effects during early exposure to tobacco may relate to dependence vulnerability. We examined the association of initial nicotine sensitivity with individual difference factors of sex, other drug use history (i.e. cross-tolerance or cross-sensitization), and parental smoking status in young adult nonsmokers (N=131). Participants engaged in 4 sessions, the first 3 to assess the dose-response effects of nasal spray nicotine (0, 5, 10 μg/kg) on rewarding, mood, physiological, sensory processing, and performance effects, and the fourth to assess nicotine reinforcement using a choice procedure. Men had greater initial sensitivity than women to some self-reported effects of nicotine related to reward and incentive salience and to impairment in sensory processing, but men and women did not differ on most other effects. Prior marijuana use was associated with greater nicotine reward, nicotine reinforcement was greater in men versus women among those with prior marijuana use, and having parents who smoked was related to increased incentive salience. However, history of other drug use and parental smoking were not otherwise associated with initial nicotine sensitivity. These findings warrant replication with other methods of nicotine administration, especially cigarette smoking, and in more diverse samples of subjects naïve to nicotine. Yet, they suggest that sex differences in initial sensitivity to nicotine reward occur before the onset of dependence. They also suggest that parental smoking may not increase risk of nicotine dependence in offspring by altering initial nicotine sensitivity, and that cross-tolerance between other drugs and nicotine may not be robust in humans.
PMCID: PMC2648532  PMID: 18775605
nicotine; sensitivity; nonsmokers; reward; reinforcement; sex differences; cross-tolerance; parental smoking history
9.  Influence of a Dopamine Pathway Additive Genetic Efficacy Score on Smoking Cessation: Results from Two Randomized Clinical Trials of Bupropion 
Addiction (Abingdon, England)  2013;108(12):10.1111/add.12325.
To evaluate associations of treatment and an ‘additive genetic efficacy score’ (AGES) based on dopamine functional polymorphisms with time to first smoking lapse and point prevalence abstinence at end of treatment among participants enrolled in two randomized clinical trials of smoking cessation therapies.
Double-blind pharmacogenetic efficacy trials randomizing participants to active or placebo bupropion. Study 1 also randomized participants to cognitive-behavioral smoking cessation treatment (CBT) or this treatment with CBT for depression. Study 2 provided standardized behavioural support.
Two Hospital-affiliated clinics (Study 1), and two University-affiliated clinics (Study 2).
N=792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year.
Age, gender, Fagerström Test for Nicotine Dependence, dopamine pathway genotypes (rs1800497 [ANKK1 E713K], rs4680 [COMT V158M], DRD4 exon 3 Variable Number of Tandem Repeats polymorphism [DRD4 VNTR], SLC6A3 3' VNTR) analyzed both separately and as part of an AGES, time to first lapse, and point prevalence abstinence at end of treatment.
Significant associations of the AGES (hazard ratio = 1.10, 95% Confidence Interval [CI] = 1.06–1.14], p=0.0099) and of the DRD4 VNTR (HR = 1.29, 95%CI 1.17–1.41, p=0.0073) were observed with time to first lapse. A significant AGES by pharmacotherapy interaction was observed (β [SE]=−0.18 [0.07], p=0.016), such that AGES predicted risk for time to first lapse only for individuals randomized to placebo.
A score based on functional polymorphisms relating to dopamine pathways appears to predict lapse to smoking following a quit attempt, and the association is mitigated in smokers using bupropion.
PMCID: PMC3834197  PMID: 23941313
Bupropion; genetic; pharmacogenetic analysis; randomized clinical trial; first lapse
10.  Genetic variation in the dopamine D4 receptor (DRD4) gene and smoking cessation: follow-up of a randomised clinical trial of transdermal nicotine patch 
The pharmacogenomics journal  2007;8(2):122-128.
Smokers of European ancestry (n = 720) who participated in a double-blind, randomised, placebo-controlled trial of transdermal nicotine replacement therapy, were genotyped for two functional polymorphisms (variable number of tandem repeats (VNTR) and a C to T transition at position −521 (C-521T)) in the dopamine D4 receptor gene (DRD4) gene. Logistic regression models of abstinence at 12- and 26-week follow-ups were carried out separately for each polymorphism. For the DRD4 VNTR models, the main effect of treatment was significant at both 12-week (P = 0.001) and 26-week (P = 0.006) follow-ups, indicating an increased likelihood of successful cessation on active nicotine replacement therapy transdermal patch relative to placebo. The main effect of DRD4 VNTR genotype was associated with abstinence at 12-week follow-up (P = 0.034), with possession of one or more copies of the long allele associated with reduced likelihood of cessation (17 vs 23%), but this effect was not observed at 26-week follow-up. For the DRD4 C-521T models, no main effect or interaction terms involving genotype were retained in the models at either 12- or 26-week follow-up. These data are consistent with observations from studies of the DRD2 gene that genetic variants related to relatively decreased dopaminergic tone in the mesocorticolimbic system are associated with increased risk for relapse to smoking following a cessation attempt.
PMCID: PMC2288552  PMID: 17387332
DRD4; VNTR; C-521T; smoking cessation; nicotine replacement therapy
11.  Differential Neural Response to Alcohol Priming and Alcohol Taste Cues Is Associated With DRD4 VNTR and OPRM1 Genotypes 
Studies suggest that polymorphisms in the D4 dopamine receptor (DRD4) and opioid receptor, μ1 (OPRM1) genes are involved in differential response to the effects of alcohol and to alcohol cues. However, to date, the mechanisms that underlie these differences remain largely unknown.
Using functional magnetic resonance imaging, hemodynamic response in mesocorticolimbic structures after exposure to alcohol tastes was contrasted with a control taste and compared between DRD4 variable number of tandem repeats (VNTR) genotypes and OPRM1 A118G genotypes. Additionally, the effects of a priming dose of alcohol on this response were examined.
The results indicated that DRD4 VNTR >7 repeat individuals (DRD4.L) had significantly greater response to alcohol cues in the orbitofrontal cortex, anterior cingulate gyrus, and striatum compared with individuals with <7 repeats (DRD4.S) prior to a priming dose of alcohol (p < 0.05), but not after a priming dose. In the OPRM1 comparisons, results showed that individuals with at least 1 copy of the OPRM1 + 118 G allele had greater hemodynamic response in mesocorticolimbic areas both before and after priming compared with those who were homozygous for the OPRM1 + 118 A allele. For the DRD4.L and OPRM1 + 118 G groups, brain response in the striatum was highly correlated with measures of alcohol use and behavior such that greater activity corresponded with greater frequency and quantity of alcohol use.
The DRD4 VNTR and OPRM1 A118G polymorphisms are associated with functional neural changes in mesocorticolimbic structures after exposure to alcohol cues. This provides evidence for the contributions of the DRD4 and OPRM1 genes in modulating neural activity in structures that are involved in the motivation to drink.
PMCID: PMC2856650  PMID: 18540916
DRD4; OPRM1; Alcohol; Craving; fMRI; Mesocorticolimbic
12.  Influences of polymorphic variants of DRD2 and SLC6A3 genes, and their combinations on smoking in Polish population 
BMC Medical Genetics  2009;10:92.
Polymorphisms in dopaminergic genes may influence cigarette smoking by their potential impact on dopamine reward pathway function. A1 allele of DRD2 gene is associated with a reduced dopamine D2 receptor density, and it has been hypothesised that A1 carriers are more vulnerable to smoking. In turn, the 9-repeat allele of dopamine transporter gene (SLC6A3) has been associated with a substantial reduction in dopamine transporter, what might result in the higher level of dopamine in the synaptic cleft, and thereby protective role of this allele from smoking. In the present study we investigated whether polymorphic variants of DRD2 and SLC6A3 genes and their combinations are associated with the smoking habit in the Polish population.
Genotyping for TaqIA polymorphism of DRD2 and SLC6A3 VNTR polymorphism was performed in 150 ever-smokers and 158 never-smokers. The association between the smoking status and smoking phenotypes (related to the number of cigarettes smoked daily and age of starting regular smoking), and genotype/genotype combinations was expressed by ORs together with 95% CI. Alpha level of 0.05, with Bonferroni correction whenever appropriate, was used for statistical significance.
At the used alpha levels no association between DRD2 and SLC6A3 genotypes and smoking status was found. However, A1 allele carriers reported longer abstinence periods on quitting attempts than non-carriers (p = 0.049). The ORs for heavier smoking were 0.38 (0.17-0.88), p = 0.023, and 0.39 (0.17-0.88), p = 0.021 in carriers compared to non-carriers of A1 or *9 allele, respectively, and the OR for this smoking phenotype was 8.68 (2.47-30.46), p = 0.0005 for the A1-/9- genotype combination, relatively to the A1+/9+. Carriers of *9 allele of SLC6A3 had over twice a lower risk to start smoking before the age of 20 years compared to non-carriers (sex-adjusted OR = 0.44; 95% CI: 0.22-0.89; p = 0.0017), and subjects with A1-/9- genotype combination had a higher risk for staring regular smoking before the age of 20 years in comparison to subjects with A1+/9+ genotype combination (sex-adjusted OR = 3.79; 95% CI:1.03-13.90; p = 0.003).
Polymorphic variants of DRD2 and SLC6A3 genes may influence some aspects of the smoking behavior, including age of starting regular smoking, the level of cigarette consumption, and periods of abstinence. Further large sample studies are needed to verify this hypothesis.
PMCID: PMC2758863  PMID: 19761593
13.  Dopamine genes and nicotine dependence in treatment seeking and community smokers 
We utilized a cohort of 828 treatment seeking self-identified white cigarette smokers (50% female) to rank candidate gene single nucleotide polymorphisms (SNPs) associated with the Fagerström Test for Nicotine Dependence (FTND), a measure of nicotine dependence which assesses quantity of cigarettes smoked and time- and place-dependent characteristics of the respondent’s smoking behavior. 1123 SNPs at 55 autosomal candidate genes, nicotinic acetylcholine receptors and genes involved in dopaminergic function, were tested for association to baseline FTND scores adjusted for age, depression, education, sex and study site. SNP P values were adjusted for the number of transmission models, the number of SNPs tested per candidate gene, and their intragenic correlation. DRD2, SLC6A3 and NR4A2 SNPs with adjusted P values < 0.10 were considered sufficiently noteworthy to justify further genetic, bioinformatic and literature analyses. Each independent signal among the top-ranked SNPs accounted for ~1% of the FTND variance in this sample. The DRD2 SNP appears to represent a novel association with nicotine dependence. The SLC6A3 SNPs have previously been shown to be associated with SLC6A3 transcription or dopamine transporter density in vitro, in vivo and ex vivo. Analysis of SLC6A3 and NR4A2 SNPs identified a statistically significant gene-gene interaction (P=0.001), consistent with in vitro evidence that the NR4A2 protein product (NURR1) regulates SLC6A3 transcription. A community cohort of N=175 multiplex ever smoking pedigrees (N=423 ever smokers) provided nominal evidence for association with the FTND at these top ranked SNPs, uncorrected for multiple comparisons.
PMCID: PMC3558036  PMID: 19494806
dopamine transporter; Fagerström Test for Nicotine Dependence; single nucleotide polymorphism; candidate gene association scan; gene-gene interaction
14.  Dopamine Genes (DRD2/ANKK1-TaqA1 and DRD4-7R) and Executive Function: Their Interaction with Obesity 
PLoS ONE  2012;7(7):e41482.
Obesity is a multifactorial disease caused by the interaction between genotype and environment, and it is considered to be a type of addictive alteration. The A1 allele of the DRD2/ANKK1-TaqIA gene has been associated with addictive disorders, with obesity and with the performance in executive functions. The 7 repeat allele of the DRD4 gene has likewise been associated with the performance in executive functions, as well as with addictive behaviors and impulsivity. Participants were included in the obesity group (N = 42) if their body mass index (BMI) was equal to or above 30, and in the lean group (N = 42) if their BMI was below 25. The DRD2/ANKK1-TaqIA and DRD4 VNTR polymorphisms were obtained. All subjects underwent neuropsychological assessment. Eating behavior traits were evaluated. The ‘DRD2/ANKK1-TaqIA A1-allele status’ had a significant effect on almost all the executive variables, but no significant ‘DRD4 7R-allele status’ effects were observed for any of the executive variables analyzed. There was a significant ‘group’ x ‘DRD2/ANKK1-TaqIA A1-allele status’ interaction effect on LN and ‘group’ x ‘DRD4 7R-allele status’ interaction effect on TMT B-A score. Being obese and a carrier of the A1 allele of DRD2/ANKK1-TaqIA or the 7R allele of DRD4 VNTR polymorphisms could confer a weakness as regards the performance of executive functions.
PMCID: PMC3405092  PMID: 22848508
15.  Genetic Variants and Early Cigarette Smoking and Nicotine Dependence Phenotypes in Adolescents 
PLoS ONE  2014;9(12):e115716.
While the heritability of cigarette smoking and nicotine dependence (ND) is well-documented, the contribution of specific genetic variants to specific phenotypes has not been closely examined. The objectives of this study were to test the associations between 321 tagging single-nucleotide polymorphisms (SNPs) that capture common genetic variation in 24 genes, and early smoking and ND phenotypes in novice adolescent smokers, and to assess if genetic predictors differ across these phenotypes.
In a prospective study of 1294 adolescents aged 12–13 years recruited from ten Montreal-area secondary schools, 544 participants who had smoked at least once during the 7–8 year follow-up provided DNA. 321 single-nucleotide polymorphisms (SNPs) in 24 candidate genes were tested for an association with number of cigarettes smoked in the past 3 months, and with five ND phenotypes (a modified version of the Fagerstrom Tolerance Questionnaire, the ICD-10 and three clusters of ND symptoms representing withdrawal symptoms, use of nicotine for self-medication, and a general ND/craving symptom indicator).
The pattern of SNP-gene associations differed across phenotypes. Sixteen SNPs in seven genes (ANKK1, CHRNA7, DDC, DRD2, COMT, OPRM1, SLC6A3 (also known as DAT1)) were associated with at least one phenotype with a p-value <0.01 using linear mixed models. After permutation and FDR adjustment, none of the associations remained statistically significant, although the p-values for the association between rs557748 in OPRM1 and the ND/craving and self-medication phenotypes were both 0.076.
Because the genetic predictors differ, specific cigarette smoking and ND phenotypes should be distinguished in genetic studies in adolescents. Fifteen of the 16 top-ranked SNPs identified in this study were from loci involved in dopaminergic pathways (ANKK1/DRD2, DDC, COMT, OPRM1, and SLC6A3).
Dopaminergic pathways may be salient during early smoking and the development of ND.
PMCID: PMC4278712  PMID: 25545355
16.  Blockade of Dopamine D4 Receptors Attenuates Reinstatement of Extinguished Nicotine-Seeking Behavior in Rats 
Neuropsychopharmacology  2011;37(3):685-696.
Since cloning of the dopamine receptor D4 (DRD4), its role in the brain has remained unclear. It has been reported that polymorphism of the DRD4 gene in humans is associated with reactivity to cues related to tobacco smoking. However, the role of DRD4 in animal models of nicotine addiction has seldom been explored. In our study, male Long-Evans rats learned to intravenously self-administer nicotine under a fixed-ratio (FR) schedule of reinforcement. Effects of the selective DRD4 antagonist L-745,870 were evaluated on nicotine self-administration behavior and on reinstatement of extinguished nicotine-seeking behavior induced by nicotine-associated cues or by priming injections of nicotine. L-745,870 was also tested on reinstatement of extinguished food-seeking behavior as a control. In addition, the selective DRD4 agonist PD 168,077 was tested for its ability to reinstate extinguished nicotine-seeking behavior. Finally, L-745,870 was tested in Sprague Dawley rats trained to discriminate administration of 0.4 mg/kg nicotine from vehicle under an FR schedule of food delivery. L-745,870 significantly attenuated reinstatement of nicotine-seeking induced by both nicotine-associated cues and nicotine priming. In contrast, L-745,870 did not affect established nicotine self-administration behavior or reinstatement of food-seeking behavior induced by food cues or food priming. L-745,870 did not produce nicotine-like discriminative-stimulus effects and did not alter discriminative-stimulus effects of nicotine. PD 168,077 did not reinstate extinguished nicotine-seeking behavior. As DRD4 blockade by L-745,870 selectively attenuated both cue- and nicotine-induced reinstatement of nicotine-seeking behavior, without affecting cue- or food-induced reinstatement of food-seeking behavior, DRD4 antagonists are potential therapeutic agents against tobacco smoking relapse.
PMCID: PMC3260983  PMID: 22030716
dopamine receptor D4; receptor antagonist; nicotine self-administration; reinstatement of nicotine-seeking behavior; tobacco smoking; relapse; addiction & substance abuse; animal models; dopamine; psychopharmacology; dopamine receptor; D4 receptor antagonist; nicotine self-administration; reinstatement of nicotine-seeking behavior; tobacco smoking
17.  Neurogentics of Dopaminergic Receptor Super-sensitivity in Activation of Brain Reward Circuitry and Relapse: Proposing “Deprivation-Amplification Relapse Therapy” (DART) 
Postgraduate medicine  2009;121(6):176-196.
Background and Hypothesis
It is well known that after prolonged abstinence, individuals who imbibe or use their drug of choice experience a powerful euphoria that precipitates serious relapse. While a biological explanation for this conundrum has remained elusive, we hypothesize that this clinically observed “super sensitivity” might be tied to genetic dopaminergic polymorphisms. Another therapeutic conundrum relates to the paradoxical finding that the dopaminergic agonist bromocriptine induces stronger activation of brain reward circuitry in individuals who carry the DRD2 A1 allele compared to DRD2 A2 allele carriers. Based upon the fact that carriers of the A1 allele relative to the A2 allele of the DRD2 gene have significantly lower D2 receptor density, a reduced sensitivity to dopamine agonist activity would be expected in the former. Thus, it is perplexing that with low D2 density there is an increase in reward sensitivity with the dopamine agonist bromocriptine. Moreover, under chronic or long-term therapy, the potential proliferation of D2 receptors with bromocriptine has been shown in vitro. This seems to lead to a positive outcome and significantly better treatment compliance only in A1 carriers.
Proposal and Conclusion
We propose that low D2 receptor density and polymorphisms of the D2 gene are associated with risk for relapse of substance abuse including alcohol dependence, heroin craving, cocaine dependence, methamphetamine abuse, nicotine sensitization, and glucose craving. With this in mind, we suggest a putative physiological mechanism that may help to explain the enhanced sensitivity following intense acute dopaminergic D2 receptor activation: “denervation supersensitivity.” Thus, the administration of dopamine D2 agonists would target D2 sensitization and attenuate relapse, especially in D2 receptor A1 allele carriers. This hypothesized mechanism is supported by clinical trials utilizing the amino-acid neurotransmitter precursors, enkephalinase and catechol-O-methyl-transferase (COMT) enzyme inhibition, which have resulted in attenuated relapse rates in Reward Deficiency Syndrome (RDS) probands. Future warranted translational research with positive outcome showing prevented or lower relapse in RDS will ultimately support the proposed concept, which we term “Deprivation-Amplification Relapse Therapy (DART).”
PMCID: PMC3656125  PMID: 19940429
18.  Clinical and pharmacogenetic determinants for the discontinuation of non-ergoline dopamine agonists in Parkinson’s disease 
To identify determinants for the discontinuation of non-ergoline dopamine agonist (DA) treatment in patients with Parkinson’s disease (PD) and to identify genetic determinants in genes encoding dopamine receptor (DR)D2 and DRD3 in a exploratory analysis.
Patients included were first-time users of the non-ergoline DA ropinirole or pramipexole who had been diagnosed with PD before 2005. Treatment discontinuation was defined as a gap of 180 days or more between two refills of the DA. Non-genetic determinants for discontinuation were studied in the overall population, and genetic determinants [DRD2 141C Ins/Del, DRD2 (CA)n STR, DRD2 TaqIA, DRD3 MscI single nucleotide polymorphism (SNP) and DRD3 MspI SNP] were studied in a subgroup. Cox proportional hazard analysis was used to estimate the hazard ratios (HR) for the discontinuation of non-ergoline DA treatment.
The study population comprised 90 patients. Apomorphine use was associated with non-ergoline DA discontinuation, although the apomorphine group consisted only of three patients [HR 6.26; 95% confidence interval (CI) 1.85–21.2]. Daily levodopa dosages between 500 and 1000 mg were positively associated with discontinuation (HR 2.31; 95% CI 1.08–4.93). Included in the exploratory pharmacogenetic analysis were 38 patients. The absence of a 15× DRD2 CA repeat allele was significantly related with a decreased discontinuation of non-ergoline treatment (HR 0.23; 95% CI 0.07–0.81). The DRD3 MspI polymorphism showed a non-significant allele dose effect, suggestive of a causal relationship.
This study identified apomorphine use and levodopa dosages between 500 and 1000 mg as non-genetic and the 15× DRD2 CA repeat allele as genetic determinants for the discontinuation of non-ergoline DA treatment in patients with PD. More research is needed to replicate these findings.
PMCID: PMC2778789  PMID: 19669131
Determinants; Discontinuation; Dopamine agonists; Dopamine receptors; Parkinson’s disease; Pharmacogenetics; Pramipexole; Ropinirole
19.  DRD and GRIN2B polymorphisms and their association with the development of impulse control behaviour among Malaysian Parkinson’s disease patients 
BMC Neurology  2015;15:59.
Impulse control disorder (ICD) and behaviours (ICB) represent a group of behavioural disorders that have become increasingly recognised in Parkinson’s disease (PD) patients who previously used dopaminergic medications, particularly dopamine agonists and levodopa. It has been suggested that these medications can lead to the development of ICB through the abnormal modulation of dopaminergic transmission and signalling in the mesocorticolimbic dopaminergic system. Several studies have reported an association between polymorphisms in the dopamine receptor (DRD) and N-methyl-D-aspartate 2B (GRIN2B) genes with the development of ICB in PD (PD-ICB) patients. Thus, this study aimed to investigate the association of selected polymorphisms within the DRD and GRIN2B genes with the development of ICB among PD patients using high resolution melt (HRM) analysis.
We used high resolution melt (HRM) analysis to genotype 11 polymorphisms in 5 DRD genes [DRD1 (rs4532, rs4867798 and rs265981), DRD2 (ANKK1 rs1800497, rs104894220 and rs144999500), DRD3 (rs3732783 and rs6280), DRD4 (rs1800443), and DRD5 (rs144132215)] and 1 polymorphism in GRIN2B (rs7301328) in PD patients with (cases, n = 52) and without (controls, n = 39) ICB. Cases were obtained from two tertiary movement disorder centres [UKMMC (n = 9) and UMMC (n = 43)]. At both centres, the diagnosis of ICB was made using the QUIP questionnaire. Controls were recruited from PD patients who attended UKMMC and were found to be negative for ICB using the QUIP questionnaire.
The HRM analysis showed that 7 of 11 polymorphisms [DRD1 (rs4532, rs4867798, and rs265981), DRD2 (ANKK1 rs1800497), DRD3 (rs3732783 and rs6280), and GRIN2B (rs7301328)] exhibited a clear distinction between wild-type and variant alleles. Variants of DRD2/ANKK1 rs1800497 (OR = 3.77; 95% CI, 1.38-10.30; p = 0.0044), DRD1 rs4867798 (OR = 24.53; 95% CI, 1.68-357.28; p = 0.0054), DRD1 rs4532 (OR = 21.33; 95% CI, 1.97-230.64; p = 0.0024), and GRIN2B rs7301328 (OR = 25.07; 95% CI, 1.30-483.41; p = 0.0097) were found to be associated with an increased risk of developing ICB among PD patients.
Our findings suggest that polymorphisms in dopamine [DRD1 (rs4532 and rs4867798) and DRD2/ANKK1 rs1800497] and glutamate (GRIN2B rs7301328) receptor genes confer increased risk of ICB development among PD patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-015-0316-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4417293  PMID: 25896831
High resolution melt analysis; DNA polymorphism; N-methyl-D-aspartate 2B; Dopamine receptor
20.  Association of DRD4 uVNTR and TP53 codon 72 polymorphisms with schizophrenia: a case-control study 
BMC Medical Genetics  2009;10:147.
The tumour supressor gene TP53 is thought to be involved in neural apoptosis. The polymorphism at codon 72 in TP53 and the long form variants of the upstream variable number of tandem repeats (uVNTR) polymorphism in the dopamine D4 receptor (DRD4) gene are reported to confer susceptibility to schizophrenia.
We recruited 934 patients with schizophrenia and 433 healthy individuals, and genotyped the locus of the TP53 codon 72 and DRD4 uVNTR polymorphisms by combining the polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP) with direct sequencing.
No significant differences were found in the frequency of the genotype of the TP53 codon72 polymorphism between patients with schizophrenia and their controls. However, the long form alleles (≥ 5 repeats) of the DRD4 uVNTR polymorphism were more frequent in patients with schizophrenia than in controls (p = 0.001). Hence, this class of alleles might be a risk factor for enhanced vulnerability to schizophrenia (odds ratio = 3.189, 95% confidence interval = 1.535-6.622). In the logistic regression analysis, the long form variants of the DRD4 polymorphism did predict schizophrenia after the contributions of the age and gender of the subjects were included (p = 0.036, OR = 2.319), but the CC and GG genotypes of the codon 72 polymorphism of TP53 did not.
The long form variants of the uVNTR polymorphism in DRD4 were associated with schizophrenia, in a manner that was independent of the TP53 codon 72 polymorphism. In addition, given that the genetic effect of the TP53 codon 72 polymorphism on the risk of developing schizophrenia was very small, this polymorphism is unlikely to be associated with schizophrenia. The roles that other single nucleotide polymorphisms (SNPs) in the TP53 gene or in other apoptosis-related genes play in the synaptic dysfunction involved in the pathogenesis of schizophrenia should be investigated.
PMCID: PMC2808306  PMID: 20040103
21.  Association analyses for dopamine receptor gene polymorphisms and weight status in a longitudinal analysis in obese children before and after lifestyle intervention 
BMC Pediatrics  2013;13:197.
Dopamine receptors are involved in midbrain reward circuit activation. Polymorphisms in two dopamine receptor genes, DRD2 and DRD4, have been associated with altered perception of food reward and weight gain. The objective of this study was to determine whether the same risk alleles were associated with overweight/obesity and with lower reduction of overweight after a 1-year lifestyle intervention.
In a longitudinal study the association of polymorphisms in DRD2 (rs18000497, risk allele: T, formerly A1 allele at the TaqI A1 polymorphism) and DRD4 (variable number of tandem repeats (VNTR); 48 bp repeat in exon III; risk alleles: 7 repeats or longer: 7R+) was tested on weight loss success following a 1-year lifestyle childhood obesity intervention (OBELDICKS). An additional exploratory cross-sectional case-control study was performed to compare the same DRD polymorphisms in these overweight/obese children and adolescents versus lean adult controls. Subjects were 423 obese and 28 overweight children participating in lifestyle intervention (203 males), age median 12.0 (interquartile range 10.0–13.7) years, body mass index - standard deviation score (BMI-SDS) 2.4 ± 0.5; 583 lean adults (232 males); age median 25.3 (interquartile range 22.5–26.8) years, BMI 19.1 ± 1.9 kg/m2. BMI, BMI-SDS and skinfold thickness measures were assessed at baseline and after 1 year; genotyping was performed for DRD2 risk variant rs1800497 and DRD4 exon III VNTR.
The DRD2 genotype had a nominal effect on success in the weight loss intervention. The weakest BMI-SDS reduction was in children homozygous for two rs1800497 T-alleles (n = 11) compared to the combined group with zero (n = 308) or one (n = 132) rs1800497 T-allele (-0.08 ± 0.36 vs. -0.28 ± 0.34; p < 0.05). There was no association between the DRD4 VNTR alleles and genotypes and success in the weight loss intervention. No associations of the risk alleles of the DRD2 and DRD4 polymorphisms and obesity were observed in the cross-sectional part of the study.
We did not find association between polymorphisms in DRD2 and DRD4 genes and weight status. However, obese carriers of two DRD2 rs1800497 T-alleles may be at risk for weak responses to lifestyle interventions aimed at weight reduction.
Trial registration
Obesity intervention program “Obeldicks” is registered at (NCT00435734).
PMCID: PMC4219494  PMID: 24283216
Dopamine receptor polymorphisms; Obesity; Lifestyle intervention; Weight reduction
22.  The CHRNA3 rs578776 Variant is Associated with an Intrinsic Reward Sensitivity Deficit in Smokers 
A compromised brain reward system has been postulated as a key feature of drug dependence. We examined whether several polymorphisms of genes found to regulate nicotinic acetylcholine receptor (nAChR) and dopamine expression were related to an intrinsic reward sensitivity (IRS) deficit we previously identified among a subgroup of smokers using event-related potentials (ERPs). We examined genetic polymorphisms within the CHRNA5-A3-B4 gene cluster (CHRNA3 rs578776, CHRNA5 rs16969968, LOC123688 rs8034191, and CHRNA3 rs1051730), the ANKK1 gene (rs1800497), and the D2 dopamine receptor gene (DRD2 rs1079597, DRD2 rs1799732) from 104 smokers of European ancestry in a smoking cessation trial. Prior to treatment, we recorded ERPs evoked by emotional (both pleasant and unpleasant), neutral, and cigarette-related pictures. Smokers were assigned to two groups (IRS+/IRS−) based on the amplitude of the late positive potential (LPP) component to the pictures, a neural marker of motivational salience. Smokers (n = 42) with blunted brain responses to intrinsically rewarding (pleasant) pictures and enhanced responses to cigarette pictures were assigned to the IRS− group, while smokers (n = 62) with the opposite pattern of LPP responding were assigned to the IRS+ group. Carriers of the protective minor T allele (T/T, C/T) of the CHRNA3 rs578776 were less likely to be members of the IRS− group than those homozygous for the at-risk C allele (C/C). The CHRNA3 rs578776 polymorphism did not differ on questionnaires of nicotine dependence, depressed mood, or trait affective disposition and did not predict abstinence at 6 months after the quit date. These results suggest that polymorphisms of genes influencing nAChR expression are related to an endophenotype of reward sensitivity in smokers.
PMCID: PMC3779859  PMID: 24065931
nAChR; DRD2; nicotine; reward sensitivity; ERP; LPP; smoking cessation; genetics
23.  Nicotine Abstinence-induced Cerebral Blood Flow Changes by Genotype 
Neuroscience letters  2008;438(3):275-280.
This study explored whether functional genetic variants previously associated with nicotine dependence are associated with regional cerebral blood flow (rCBF) changes during nicotine abstinence (compared to satiety; smoking as usual). Thirteen smokers participating in a prior arterial spin labeled (ASL) perfusion MRI study were scanned on two occasions (after >12 hours abstinence vs. satiety) [24], and were genotyped for variants in the dopamine D2 receptor (DRD2-141 Ins/DelC; DRD2 C957T); a dopamine metabolizing enzyme (COMT val/val), and the mu opioid receptor (OPRM1 A118G). Significantly greater CBF increases were found in regions previously linked with cigarette cravings among carriers of the DelC variant of DRD2-141 and among the COMT val/val group. Smokers with TT genotypes for the DRD2 C957T exhibited less change in rCBF in abstinence relative to satiety, compared to those with CC or CT genotypes. Finally, smokers with OPRM1 AA genotypes showed significant increases in CBF in regions associated previously with cigarette cravings. While preliminary, these results suggest a neural mechanism through which these genetic variants may be linked with nicotine dependence, and provide further support for increased biological vulnerability in these subgroups of smokers.
PMCID: PMC2474789  PMID: 18499348
perfusion MRI; nicotine; addiction; genetics
24.  Role of Nicotine Dependence in the Association between the Dopamine Receptor Gene DRD3 and Major Depressive Disorder 
PLoS ONE  2014;9(6):e98199.
The aims of this study were to analyze associations of dopamine receptor genes (DRD1-5) with Major Depressive Disorder (MDD) and nicotine dependence (ND), and to investigate whether ND moderates genetic influences on MDD.
The sample was ascertained from the Finnish Twin Cohort. Twin pairs concordant for smoking history were recruited along with their family members, as part of the multisite Nicotine Addiction Genetics consortium. Genetic association analyses were based on 1428 adults. Total of 70 tagging single nucleotide polymorphisms within the dopamine receptor genes were genotyped and analyzed for association with MDD, ND, and MD-ND co-morbidity. Individual level logistic regression analyses were based on 1296 adults with data on ND and MDD diagnoses, as well as on dopamine receptor genotypes adjusted for sex, age, and alcohol use. Four independent samples, such as population-based and case-control samples, were used for replication.
Rs2399496, located 1.5 kb downstream of DRD3, showed suggestive association for MDD (p = 0.00076) and significant association for MDD-ND co-morbidity (p = 0.000079). Suggestive gene-(rs2399496) by-ND-interaction justified analyses by genetic risk variant and ND status. Individuals with ND and two minor alleles (AA) of rs2399496 had almost six-fold risk for MDD (OR 5.74, 95%CI 3.12–10.5, p = 9.010e-09) compared to individuals without ND and with two major alleles (TT).
Significant association between a variant downstream of DRD3 and a co-morbid MDD-ND phenotype was detected. Our results further suggest that nicotine dependence may potentiate the influence of the DRD3 genetic variant on MDD.
PMCID: PMC4057087  PMID: 24927283
25.  Polymorphisms of the µ-opioid receptor and dopamine D4 receptor genes and subjective responses to alcohol in the natural environment 
Journal of abnormal psychology  2010;119(1):115-125.
Polymorphisms of the µ-opioid receptor (OPRM1) and dopamine D4 receptor (DRD4) genes are associated with subjective responses to alcohol and urge to drink under laboratory conditions. This study examines these associations in the natural environment using ecological momentary assessment (EMA). Participants were non-treatment seeking heavy drinkers (n = 112, 52% female, 61% alcohol dependent) who enrolled in a study of naltrexone effects on craving and drinking in the natural environment. Data were culled from five consecutive days of drinking reports prior to medication randomization. Analyses revealed that, after drinking, carriers of the Asp40 allele of the OPRM1 gene reported higher overall levels of vigor and lower levels negative mood, as compared to homozygotes for the Asn40 variant. Carriers of the long allele (i.e., ≥ 7 tandem repeats) of the DRD4 endorsed greater urge to drink than homozygotes for the short allele. Effects of OPRM1 and DRD4 VNTR genotypes appear to be alcohol dose-dependent. Specifically, carriers of the DRD4-L allele reported slight decreases in urge to drink at higher levels of estimated Blood Alcohol Concentration (eBAC) and Asp40 carriers reported decreases in vigor and increases in negative mood as eBAC rose, as compared to carriers of the major allele for each gene. Self-reported vigor and urge to drink were positively associated with alcohol consumption within the same drinking episode. This study extends findings on subjective intoxication, urge to drink, and their genetic bases from controlled laboratory to naturalistic settings.
PMCID: PMC3703617  PMID: 20141248
OPRM1; DRD4; urge to drink; alcohol; EMA

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