Gene Polymorphism(s) Study Findings Reference Comment
D2 dopamine receptor gene (DRD2) SNP rs: 1800497 TaqA1 allele associates with sever alcoholism Blum et al. [24] First study to associate with alcoholism (called reward gene)
  ANKKI -p.Glu713Lys DRD2 Taq1A RFLP is a single nucleotide polymorphism (SNP) that causes an amino acid substitution within the 11th ankyrin repeat of ANKK1 Neville et al.[62] The ANKKI gene is a reflection of DRD2 A1 allele.
  SNP rs: 1800497 This SNP has been found to predict future RDS behaviors as high as 74%. Blum et al. [63] using Bayesian analysis
  SNP rs: 1800497 Presence of the A1+ genotype (A1/A1, A1 /A2) compared to the A– genotype (A2/A2), is associated with reduced density Noble et al. [25] This reduction causes hypodopaminergic functioning in the dopamine reward pathway.
  SNP rs: 6277 at exon 7 T+ allele associates with alcohol dependence. Hoffman et al.[64] Associates with drug seeking behavior and other RDS behaviors
  SNP rs: 1800497 10 year follow up that carriers of the DRD2 A1 allele have a higher rate of mortality compared to carriers of the A2 allele in alcohol dependent individuals Dahlgren et al. [65] Taq I A1 allele and a substantially increased relapse rate
  DRD2-haplotypes I-C-G-A2 and I-C-A-A1 Confirmed the hypothesis that haplotypes, which are supposed to induce a low DRD2 expression, are associated with alcohol dependence. Kraschewski et al. [66] High frequency of haplotype was associated with Cloninger Type 2 and family history of alcoholism.
  SNP rs: 1800497 Genotype analysis showed a significantly higher frequency for the TaqIA polymorphism among the addicts (69.9%) compared to control subjects (42.6%; Fisher's exact χ(2), p < .05). Teh et al. [67] The addicts had higher scores for novelty seeking (NS) and harm avoidance (HA) personality traits
D4 dopamine receptor gene (DRD4) DRD4 - The 7 repeat (7R) VNTR The length of the D4 dopamine receptor (DRD4) exon 3 variable number of tandem repeats (VNTR) affects DRD4 functioning by modulating the expression and efficiency of maturation of the receptor. Van Tol [68] The 7 repeat (7R) VNTR requires significantly higher amounts of dopamine to produce a response of the same magnitude as other size VNTRs
  120bp duplication, -616C/G, and -521C/T Strong finding of -120 bp duplication allele frequencies with schizophrenia (p = 0.008);-521 C/Tpolymorphismis associated with heroin addiction. Lai et al. [69] This reduced sensitivity or “dopamine resistance” leads to hypodopaminergic functioning. Thus 7R VNTR has been associated with substance –seeking behavior
  DRD4 7-repeat allele A number of putative risk alleles using survival analysis revealed that by 25 years of age 76% of subjects with a DRD4 7-repeat allele were estimated to have significantly more persistent ADHD compared with 66% of Subjects without the risk allele. Biederman et al. [70] Findings suggest that the DRD4 7-repeat allele is associated with a more persistent course of ADHD
  7-repeat allele of the dopamine D(4) receptor gene (DRD4) Although the association between ADHD and DRD4 is small, these results suggest that it is real. Faraone et al. [71] For both the case-control and family-based studies, the authors found 1) support for the association between ADHD and DRD4, 2) no evidence that this association was accounted for by any one study, and 3) no evidence for publication bias.
  dopamine D4 receptor (DRD4) exon 3 polymorphisms (48 bp VNTR) Found significant differences in the short alleles (2-5 VNTR) frequencies between controls and patients with a history of delirium tremens and/or alcohol seizures (p = 0.043). Grzywacz et al. [72] A trend was also observed in the higher frequency of short alleles amongst individuals with an early age of onset of alcoholism (p = 0.063).
  dopamine D4 receptor (DRD4) -7 repeat allele Show that the 7-repeat allele is significantly over-represented in the opioid-dependent cohort and confers a relative risk of 2.46 Kotler et al. [73] This is the first report of an association between a specific genetic polymorphism and opioid addiction.
Dopamine Transporter gene (DAT1) Localized to chromosome 5p15.3. Moreover, within 3 noncoding region of DAT1 lies a VNTR polymorphism -9 repeat (9R) VNTR The 9 repeat (9R) VNTR has been shown to influence gene expression and to augment transcription of the dopamine transporter protein Byerley et al.[74] Having this variant results in an enhanced clearance of synaptic dopamine, yielding reduced levels of dopamine to activate postsynaptic neurons
  R9 repeat (9R) VNT DAT1, genotype 9/9 was associated with early opiate addiction Galeeva et al. [75] The combination of SERT genotype 10/10 with DAT1 genotype 10/10 was shown to be a risk factor of opiate abuse under 16 years of age.
  exon 15 rs27072 and VNTR (DAT), promoter VNTR and rs25531 The haplogenotypes 6-A-10/6-G-10 and 5-G-9/5-G-9 were more often present in type 2 alcoholics as compared with type 1 alcoholics [odds ratio (OR): 2.8], and controls (OR: 5.8), respectively. Reese et al. [76] In a typology proposed by Cloninger on the basis of adoption studies, a subgroup has been classified as type 2 with patients having high genetic loading for alcoholism, an early onset of alcoholism, a severe course, and coexisting psychiatric problems consisting of aggressive tendencies or criminality
  VNTR polymorphism at the dopamine transporter locus (DAT1) 480-bp DAT1 allele Using the haplotype-based haplotype relative risk (HHRR) method revealed significant association between ADHD/UADD and the 480-bp DAT1 allele (chi 2 7.51, 1 df, p = 0.006). Cook et al.[77] While there have been some inconsistencies associated with the earlier results the evidence is mounting in favor of the view that the 10R allele of DAT is associated with high risk for ADHD in children and in adults alike
  dopamine transporter (DAT1) variable number tandem repeats (VNTR), genotypes- both 9 and 10-repeat alleles The non-additive association for the 10-repeat allele was significant for hyperactivity-impulsivity (HI) symptoms. However, consistent with other studies, exploratory analyses of the non-additive association of the 9-repeat allele of DAT1 with HI and oppositional defiant disorder (ODD) symptoms also were significant. Lee et al.[78] The inconsistent association between DAT1 and child behavior problems in this and other samples may reflect joint influence of the 10-repeat and 9-repeat alleles.
Catechol-O-methyltransferase (COMT) COMTVal158Met and DRD2 Taq1A genotypes COMTVal158Met and DRD2 Taq1A may affect the intermediate phenotype of central dopamine receptor sensitivity. Schellekens et al.[79] COMTVal158Met and DRD2 Taq1A may confer their risk of alcohol dependence through reduced dopamine receptor sensitivity in the prefrontal cortex and hindbrain, respectively.
  The functional polymorphism(COMTVal108/158Met) affectsCOMTactivity, with the valine (Val) variant associated with higher and the methionine (Met) variant with lowerCOMTactivity Male alcoholic suicide attempters, compared to male non-attempters, had the higher frequency of Met/Met genotype or Met allele, and significantly (Kruskal-Wallis ANOVA on ranks and Mann-Whitney test) higher aggression and depression scores. Nedic et al. [80] These results confirmed the associations between Met allele and aggressive behaviour or violent suicide attempts in various psychiatric diagnoses, and suggested that Met allele of theCOMTVal108/158 Met might be used as an independent biomarker of suicidal behaviour across different psychopathologies.
  COMTVal(158)Met variation Both controls and opiate users with Met/Met genotypes showed higher NS scores compared to those with the Val allele. Demetrovics et al. [81] Association of theCOMTpolymorphismand NS temperament scale has been shown for heroin-dependent patients and controls regardless of group status.
  A functional polymorphism COMT Val158Met) resulting in increased enzyme activity has been associated with polysubstance abuse andaddiction to heroin and methamphetamine These results suggest a significant association betweenCOMTVal158Metpolymorphismand susceptibility to cannabis dependence. Baransel et al. [82] Cannabis stimulates dopamine release and activates dopaminergic reward neurons in central pathways that lead to enhanced dependence. Catechol-O-methyl transferase (COMT) inactivates amplified extraneuronally released dopamine.
Serotonin transporter gene serotonin transporterpromoterpolymorphism[5-HTtransportergene-linked polymorphic region (5-HTTLPR)] 5-HTTLPR had age-dependent effects on alcohol, tobacco anddruguse: substance use did not differ by genotype at age 9, but at age 15, the participants with the short (s)/s genotype had higher tobacco use, and at age 18, they were more active alcohol,drugand tobacco users. Merenäkk et al. [83] Results reveal that expression ofgeneticvulnerability for substance use in children and adolescents may depend on age, gender, interaction ofgenes, and type of substance
  The short (s), low activity allele of a polymorphism (5-HTTLPR) in the serotonin transporter gene (SLC6A4) has been related to alcohol dependence The 5-HTTLPR short allele predicted adolescent's growth (slope) in alcohol use over time. Adolescents with the 5-HTTLPR short allele showed larger increase in alcohol consumption than those without the 5-HTTLPR short allele. van der Zwaluw et al. [84] 5-HTTLPR genotype was not related to the initial level (intercept) of alcohol consumption.
  triallelic 5-HTTLPR genotype: SA/SA and SA/LG compared to LA/LA Remifentanil and opioid drug had a significantly better analgesic effect in individuals with a genotype coding for low 5-HTT expression (SA/SA and SA/LG) as compared to those with high expression (LA/LA), p < 0.02. Kosek et al [85] Previously the 5-HTTLPR s-allele has been associated with higher risk of developing chronic pain conditions but in this study we show that the genotype coding for low 5-HTT expression is associated with a better analgesic effect of anopioid. The s-allele has been associated with down regulation of 5-HT1 receptors and we suggest that individuals with a desensitization of 5-HT1 receptors have an increased analgesic response to opioidsduring acute pain stimuli, but may still be at increased risk of developing chronic pain conditions.
Mu Opiate Receptor (MOR) A single nucleotide polymorphism (SNP) in the humanMORgene(OPRM1 A118G) has been shown to alterreceptor protein level in preclinical models and smokingbehaviorin humans Independent of session, smokers homozygous for the wild-type OPRM1 A allele exhibited significantly higher levels ofMORBP (ND) than smokers carrying the G allele in bilateral amygdala, left thalamus, and left anterior cingulate cortex. Ray et al. [86] Among G allele carriers, the extent of subjective reward difference (denicotinized versus nicotine cigarette) was associated significantly withMORBP(ND) difference in right amygdala, caudate, anterior cingulate cortex, and thalamus.
  Polymorphismin A118G in exon 1 and C1031G in intron 2 of theMORgene Results showed a significant association for both A118G and C1031Gpolymorphismsandopioid dependence. The G allele is more common in the heroin-dependent group (39.5% and 30.8% for A118G and C1031Gpolymorphisms, respectively) when compared to the controls (29.4% and 21.1% for A118G and C1031Gpolymorphisms, respectively). Szeto et al. [87] This study suggests that the variant G allele of both A118G and C1031Gpolymorphismsmay contribute to the vulnerability to heroin dependence.
  A118G single-nucleotide polymorphism (SNP) in exon 1 of the MOR gene (OPRM1), which encodes an amino-acid substitution, is functional andreceptorsencoded by the variant 118G allele bind the endogenous opioid peptide beta-endorphin with three-fold greater affinity than prototypereceptors. Other groups subsequently reported that this variant alters stress-responsivity in normal volunteers and also increases the therapeutic response to naltrexone (a mu-preferring opioid antagonist) in the treatment of alcohol dependence There was a significant overall association between genotypes with an 118G allele and alcohol dependence (p = 0.0074). The attributable risk for alcohol dependence in subjects with an 118G allele was 11.1% Bart et al. [88] There was no difference in A118G genotype between type 1 and type 2 alcoholics. In central Sweden, the functional variant 118G allele in exon 1 of OPRM1 is associated with an increased attributable risk for alcohol dependence.
  MOR gene knockout (KO) were examined in wild-type (+/+), heterozygote MOR KO (+/-), and homozygote MOR KO (-/-) mice on voluntary ethanol consumption Heterozygous and homozygous MOR KO mice consumed less ethanol than wild-type mice. These effects appeared to be greater in female KO mice than in male KO mice. MOR KO mice, especially females, exhibited less ethanol reward in a conditioned place preference paradigm. Hall et al. [89] These data fit with the reported therapeutic efficacy of MOR antagonists in the treatment of humanalcoholism. Allelic variants that confer differing levels of MOR expression could provide different degrees of risk for alcoholism.
GABA Beta subunit 3 GABA A receptor beta3 subunit gene (GABRB3) The G1- alleles of the GABRB3 in COAs were significantly higher than non COAs. Namkoong et al. [90] In the same study the frequency of the A1+ allele at DRD2 in the COAs was significantly higher than non COAs
  Beta 3 subunit mRNAs The levels of the beta 2 and beta 3 subunit mRNAs remains elevated at 24 hr. withdrawal from chronic ethanol. Chronic ethanol treatment increased the levels of both of these polypeptides in cerebral cortex Mhatre and Ticku [91] Chronic ethanol administration produced an up-regulation of the beta-subunit mRNA and the polypeptide expression of these subunits in rat cerebral cortex.
  A1+ (A1A1 and A1A2 genotypes) and A1- (A2A2 genotype) alleles of the DRD2 and G1+ (G1G1 and G1 non-G1 genotypes) and G1- (non-G1 non-G1 genotype) alleles of the GABRB3 gene,Study involved Mood-related alcohol expectancy (AE) and drinking refusal self-efficacy (DRSE) were assessed using the Drinking Expectancy Profile Patients with the DRD2 A1+ allele, compared with those with the DRD2 A1- allele, reported significantly lower DRSE in situations of social pressure. Similarly, lower DRSE was reported under social pressure by patients with the GABRB3 G1+ allele when compared to those with the GABRB3 G1- alleles. Patients with the GABRB3 G1+ allele also revealed reduced DRSE in situations characterized by negative affect than those with the GABRB3 G1- alleles. Patients carrying the GABRB3 G1+ allele showed stronger AE relating to negative affective change (for example, increased depression) than their GABRB3 G1- counterparts. Young et al. [92] Molecular genetic research has identified promising markers of alcohol dependence, including alleles of the D2 dopamine receptor (DRD2) and the GABAA receptor beta3 subunit (GABRB3)genes.
  Dinucleotide repeat polymorphisms of the GABA(A) receptor beta 3 subunit gene were compared to scores on the General Health Questionnaire-28 (GHQ) Analysis of GHQ subscale scores showed that heterozygotes compared to the combined homozygotes had higher scores on the somatic symptoms (p = 0.006), anxiety/insomnia (p = 0.003), social dysfunction (p = 0.054) and depression (p = 0.004) subscales. Feusner et al. [93] The present study indicates that in a population of PTSD patients, heterozygosity of the GABRB3 major (G1) allele confers higher levels of somatic symptoms, anxiety/insomnia, social dysfunction and depression than found in homozygosity.
  GABRB3 major (G1) allele & [email protected] A1 allele A significant progressive increase was observed in DRD2 A1 allelic prevalence (p = 3.1 x 10(-6)) and frequency (p = 2.7 x 10(-6)) in the order of non-alcoholics, less severe and severe alcoholics.In severe alcoholics, compared to non-alcoholics, a significant decrease was found in the prevalence (p = 4.5 x 10(-3)) and frequency (p = 2.7 x 10(-2)) of the GABRB3 major (G1) allele. Furthermore, a significant progressive decrease was noted in G1 allelic prevalence (p = 2.4 x 10(-3)) and frequency (p = 1.9 x 10(-2)) in non-alcoholics, less severe and severe alcoholics, respectively. Noble et al. [94] In sum, in the same population of non-alcoholics and alcoholics studied, variants of both the DRD2 and GABRB3 genes independently contribute to the risk for alcoholism, with the DRD2 variants revealing a stronger effect than the GABRB3 variants. However, when the DRD2 and the GABRB3 variants are combined, the risk for alcoholism is more robust than when these variants are considered separately.
MOA-A MAOA genotype Significant three-way interactions, MAOA genotype by abuse by sex, predicted dysthymic symptoms. Low-activity MAOA genotype buffered against symptoms of dysthymia in physically abused and multiply-maltreated women. Significant three-way interactions, MAOA genotype by sexualabuseby race, predicted all outcomes. Low-activity MAOA genotype buffered against symptoms of dysthymia, major depressive disorder, and alcoholabusefor sexually abused white participants.The high-activity genotype was protective in the nonwhite sexually abused group. Nikulina et al. [95] This prospective study provides evidence that MAOA interacts with child maltreatment to predict mental health outcomes.
  low-repeat MAOA allele Individuals with CUD had reductions in GMV in the orbitofrontal, dorsolateral prefrontal and temporal cortex and the hippocampus compared with controls. (2) The orbitofrontal cortex reductions were uniquely driven by CUD with low- MAOA genotype and by lifetime cocaine use. Alia-Klein et al. [96] Long-term cocaine users with the low-repeat MAOA allele have enhanced sensitivity to gray matter loss, specifically in the orbitofrontal cortex, indicating that this genotype may exacerbate the deleterious effects of cocaine in the brain.
  MAOA u-VNTR Girls, carrying the long MAOA u-VNTR variant showed a higher risk of being high alcohol consumers, whereas among boys, the short allele was related to higher alcohol consumption Nilsson et al. [97] The present study supports the hypothesis that there is a relation between MAOA u-VNTR and alcohol consumption and that this relation is modulated by environmental factors.
  30-bp repeat in the promoter region of the monoamine oxidase-A gene (MAO-A) Significant associations between cold pain tolerance and DAT-1 (p = 0.008) and MAO-A (p = 0.024) polymorphisms were found. Specifically, tolerance was shorter for carriers of allele 10 and the rarer allele 11, as compared to homozygous for allele 9, and for carriers of allele 4 (MOA) as compared to homozygous for allele 3, respectively. Treister et al. [98] These results, together with the known function of the investigated candidate gene polymorphisms, suggest that low dopaminergic activity can be associated with highpainsensitivity and vice versa.
  The Revised Psychopathy Checklist (PCL-R) has shown a moderate association with violence and as such studied with MAOAgenotyped alcoholic offenders The PCL-R total score predicts impulsive reconvictions among high-activity MAOA offenders (6.8% risk increase for every one-point increase in PCL-R total score, p = 0.015), but not among low-activity MAOA offenders, whereas antisocial behavior and attitudes predicted reconvictions in both genotypes (17% risk increase among high-activity MAOA offenders and 12.8% increase among low-activity MAOA offenders for every one-point increase in factor 2 score) Tikkanen et al. [99] Results suggest that the efficacy of PCL-R is altered by MAOA genotype, alcohol exposure, and age, which seems important to note when PCL-R is used for risk assessments that will have legal or costly preventive work consequences
  Genotyping of two functional polymorphisms in the promoter region of the serotonin transporter and monoamine oxidase-A, respectively, (5-HTT-LPR andMAOA-VNTR), was performed in a group of women with severe alcohol addiction Within the group of alcoholics, when the patients with known co-morbid psychiatric disorders were excluded, aggressive anti-social behavior was significantly linked to the presence of the high activityMAOAallele Gokturk et al. [100] The pattern of associations between genotypes of 5-HTT-LPR and MAOA-VNTR in women with severealcoholismdiffers from most corresponding studies on males.
  TheMAOAgene presents severalpolymorphisms, including a 30-bp VNTR in thepromoterregion (MAOA-uVNTR). Alleles with 3.5 and 4 repeats are 2-10 times more efficient than the 3-repeat allele The results suggest that the 3-repeat allele is associated to: (1) alcohol dependence (p < 0.05); (2) an earlier onset ofalcoholism(p < 0.01); (3) comorbid drug abuse among alcoholics (p < 0.05); and (4) a higher number of antisocial symptoms (p < 0.02). Contini et al. [101] Results confirmed previous reports showing an association of the low activity 3-repeat allele ofMAOA-uVNTRpolymorphismwith substance dependence and impulsive/antisocial behaviors. These findings in a different culture further support the influence of theMAOA-uVNTR in psychiatric disorders
Dopamine D3 The genotypes of the BDNF Val66Met and DRD3 Ser9Gly polymorphisms. BDNF regulates expression of D3 Logistic regression analysis showed a significant main effect for the Val/Val genotype of the BDNF Val66Met polymorphism (p = 0.020), which predicted bipolar-II patients. Significant interaction effects for the BDNF Val66Met Val/Val genotype and both DRD3 Ser9Gly Ser/Ser and Ser/Gly genotypes were found only in bipolar-II patients (p = 0.027 and 0.006, respectively) Lee et al. [102] Evidence that the BDNF Val66Met and DRD3 Ser9Gly genotypes interact only in bipolar-II disorder (hypomania) and that bipolar-I (Mania) and bipolar-II may be genetically distinct.
  D3R KO mice The possible interaction between morphine-induced tolerance and D3 receptors has not been investigated. Compared with wild-type (WT) mice, the dopamine D3 receptor knockout (D3R KO) mice showed pronounced hypoalgesia. The D3R KO mice clearly developed lower morphine-induced tolerance and showed attenuated withdrawal signs compared with the WT mice. Li et al. [103] These results suggest that D3 receptors regulate basal nociception and are involved in the development of morphine-induced tolerance and withdrawal.
  DNA microarrays of two different alcohol-preferring rat lines (HAD and P) and D3 receptors Data revealed an up-regulation of the dopamine D3 receptor (D3R) after 1 yr of voluntary alcohol consumption in the striatum of alcohol preferring rats that was confirmed by qRT-polymerase chain reaction. Vengeliene et al. [104] Long-term alcohol consumption leads to an up-regulation of the dopamine D3R that may contribute to alcohol-seeking and relapse. We therefore suggest that selective antagonists of this pharmacological target provide a specific treatment approach to reduce alcohol craving and relapse behavior.
  Gly9 homozygotes in comparison to Ser9 carriers of D3 receptor gene German descent and have found diminished parietal and increased frontal P300 amplitudes in Gly9 homozygotes in comparison to Ser9 carriers.Further studies should address the direct role of the DRD3 Ser9Gly polymorphism in attenuated P300 amplitudes in psychiatric disorders like schizophrenia oralcoholism. Mulert et al. [105] An important reason for the interest in P300 event-related potentials are findings in patients with psychiatric disorders like schizophrenia or alcoholism in which attenuations of the P300 amplitude are common findings.
  Dopamine receptor D3 gene BalI polymorphism Patients above the median value for cognitive impulsiveness (one of the three dimensions of the Barratt scale) were more frequently heterozygous than both alcohol-dependent patients with lower impulsiveness (OR = 2.51, p = 0.019) and than 71 healthy controls (OR = 2.32, p = 0.025). Limosin et al. [106] The D3 Receptor gene has been associated with addictive behaviors especially impulsiveness.
  Bal I polymorphism at the DRD3gen Patients with a sensation-seeking score above 24 were more frequently homozygotes for both alleles than patients with a sensation-seeking score under 24 (p = 0.038) or controls (p = 0.034). Duaux et al. [107] These results suggest that the DRD3 gene may have a role in drug dependence susceptibility in individuals with high sensation-seeking scores.
  mRNA of both DRD2 and DRD3 gene expression After a chronic schedule of intermittent bingeing on a sucrose solution, mRNA levels for the D2 dopamine receptor, and the preproenkephalin and preprotachykinin genes were decreased in dopamine-receptive regions of the forebrain, while D3 dopamine receptor mRNA was increased. The effects of sugar on mRNA levels were of greater magnitude in the nucleus accumbens than in the caudate-putamen. Spangler et al. [108] DRD3 gene accounted for 1.64% of the variance of cocaine dependence.
  MscI/BalI polymorphism of the DRD3 gene Significant decrease in the frequency of 12 heterozygotes (increase homozygosity) in subjects with cocaine dependence (29.8%) vs. controls (46.9%) (p ≤ 0.028). This percentage was still lower in those who had chronically used cocaine for more than 10 years (25%), or more than 15 years (21.5%). Comings et al. [109] The DRD2 gene had an independent and additive effect on cocaine dependence. These findings support a modest role of the DRD3 gene in susceptibility to cocaine dependence.
Source: Blum Chapter in Pharmacogenomics Ed. D. Barh (Springer) in Press with Permission
Table 1: Candidate Reward Genes and RDS - (A sampling).