Association of Alcohol or Other Drug Dependence with Alleles of the μ Opioid Receptor Gene (OPRM1)

Opioidergic neurotransmission and, specifically, the μ opioid receptor have been implicated in the reinforcing effects of a variety of drugs of abuse. Consequently, the present study examined the association of a polymorphic (CA)n repeat at the OPRM1 locus (the gene coding for the μ opioid receptor) to alcohol or drug dependence in 320 Caucasian and 108 African-American substance-dependent or control subjects. Among Caucasians, suggestion of a modest association, which could be interpreted as statistically significant ( p = 0.03), was observed between OPRMl alleles and substance (alcohol, cocaine, or opioid) dependence. Analysis by specific substance showed only a trend level association to alcohol dependence. Comparisons among African Americans yielded no evidence for association. Further studies of the association between alleles of the OPRM1 gene and substance dependence appear warranted, particularly if they use a family-based approach to control for population stratication. Phenotypes other than a broad diagnostic categorization, such as opioid antagonist effects on drinking behavior in alcoholics, may provide more consistent evidence of a role for OPRMl in behavioral variability.     

Association Analysis of a Regulatory Variation of the Serotonin Transporter Gene with Severe Alcohol Dependence

The present study tested the hypothesis that the short, low activity variant of a biallelic polymorphism in the 5'regulatory region of the human serotonin transporter (5-HTT) gene confers susceptibility to severe alcohol dependence marked by severe withdrawal symptoms. Applying a phenotype-genotype strategy, our population-based association analysis included 216 German controls and an extreme sample of 103 severely affected alcoholics who were selected from 315 German alcohol-dependent subjects by a history of alcohol withdrawal seizure or delirium. The frequency of the short allele (S) was significantly increased in the severely affected alcoholics, compared with that in the controls ( X ²= 3.87, df = 1, nominal p = 0.049). The post-hoc exploration indicated that this allelic association resulted exclusively from a significant excess of the S/S genotype in the severely affected alcoholics ( p = 0.035), suggesting a recessively acting effect. Consistently, we found a weak but significant correlation ( p = 0.013) between the frequency of the S/S genotype and severity of withdrawal symptoms (WDS): no WOS [18.3%, odds ratio (OR) = 1.16], vegetative WDS only (21.8%, OR = 1.44), and severe WDS with either withdrawal seizure only or delirium only (25.0%, OR = 1.69), and both withdrawal seizure and delirium (30.8%, OR = 2.30). Further studies are required to test whether the tentative genotype-phenotype relationship occurred by chance or reflects a real genotypic association between a recessively modifying effect of the short variant of the functional 5-HTT promoter polymorphism and alcohol withdrawal vulnerability.     

The Relationship Between Serotonin Receptor 1B Polymorphisms A-161T and Alcohol Dependence

Background:  Several studies have suggested that the serotonin receptor 1B gene ( 5HT1B ) may be important in the pathogenesis of alcohol dependence (alcoholism; ALC; AD). We examined whether 5HT1B gene A-161T polymorphisms (rs130058) are a susceptibility factor for total AD and subgroups of AD. We further explored correlation of this 5HT1B gene variant between anxiety–depression alcoholism (ANX/DEP ALC) and antisocial alcoholism (antisocial ALC) subgroups because of the high comorbidity of anxiety–depression, antisocial personality disorder, and AD.
Methods:  We recruited 522 Han Chinese in Taiwan for this study: 322 AD patients and 200 controls. The patient group was recruited primarily from medical teaching hospitals; patients with antisocial alcoholism were recruited from Taiwanese prisons. Individuals with AD were classified into 3 homogeneous clinical subgroups—pure alcoholism (pure ALC), ANX/DEP ALC, and antisocial ALC—using DSM-IV diagnosis. The 5HT1B gene A-161T polymorphism was determined using PCR–RFLP.
Results:  No significant differences in genotypic and allelic frequencies were found between controls and the total AD group or between controls and the 3 AD subgroups. However, there were significant differences in the 5HT 1B gene A-161T polymorphism at both the genotype and allelic levels between the ANX/DEP ALC and antisocial ALC subgroups.
Conclusions:  This study suggests that the 5HT1B gene A-161T polymorphism alone is not a risk factor for increasing susceptibility to either AD or its subtypes. However, 5HT1B gene A-161T polymorphisms might be one of the common genetic factors between the ANX/DEP ALC and antisocial ALC subgroups.     

Association Between Val66Met Brain-Derived Neurotrophic Factor (BDNF) Gene Polymorphism and Post-Treatment Relapse in Alcohol Dependence

Background: The purpose of this study was to examine relationships between genetic markers of central serotonin (5‐HT) and dopamine function, and risk for post‐treatment relapse, in a sample of alcohol‐dependent patients. Methods: The study included 154 patients from addiction treatment programs in Poland, who met DSM‐IV criteria for alcohol dependence. After assessing demographics, severity of alcohol use, suicidality, impulsivity, depression, hopelessness, and severity of alcohol use at baseline, patients were followed for approximately 1 year to evaluate treatment outcomes. Genetic polymorphisms in several genes (TPH2, SLC6A4, HTR1A, HTR2A, COMT, and BDNF) were tested as predictors of relapse (defined as any drinking during follow‐up) while controlling for baseline measures. Results: Of 154 eligible patients, 123 (80%) completed follow‐up and 48% (n = 59) of these individuals relapsed. Patients with the Val allele in the Val66Met BDNF polymorphism and the Met allele in the Val158Met COMT polymorphism were more likely to relapse. Only the BDNF Val/Val genotype predicted post‐treatment relapse [odds ratio (OR) = 2.62; p = 0.019], and time to relapse (OR = 2.57; p = 0.002), after adjusting for baseline measures and other significant genetic markers. When the analysis was restricted to patients with a family history of alcohol dependence (n = 73), the associations between the BDNF Val/Val genotype and relapse (OR = 5.76, p = 0.0045) and time to relapse (hazard ratio = 4.93, p = 0.001) were even stronger. Conclusions: The Val66Met BDNF gene polymorphism was associated with a higher risk and earlier occurrence of relapse among patients treated for alcohol dependence. The study suggests a relationship between genetic markers and treatment outcomes in alcohol dependence. Because a large number of statistical tests were conducted for this study and the literature on genetics and relapse is so novel, the results should be considered as hypothesis generating and need to be replicated in independent studies.     

Possibility of 5-HT3 Receptor Involvement in Alcohol Dependence: A Microdialysis Study of Nucleus Accumbens Dopamine and Serotonin Release in Rats with Chronic Alcohol Consumption

The present study was performed to examine the involvement of serotonin-3 (5-HT3) receptors in the rat nucleus accumbens (ACC) in alcohol dependence. In alcohol-treated rats, perfusion of 40 mM K⁺ and 100 mM ethanol (EtOH) through the microdialysis probe increased the extracellular levels of ACC dopamine (DA), compared with controls. Perfusion of the serotonin (5-HT) uptake inhibitor sertlarine enhanced the extracellular levels of ACC 5-HT in both groups. Increased 5-HT availability in the synaptic clefts on the ACC further activated ACC DA release in the alcohol-treated rats, in comparison with controls. In the final experiments, perfusion of the 5.0 μ M 5-HT₃ receptor agonist 2-methyl-5-HT (2-Me-5-HT) through the microdialysis probe enhanced the extracellular levels of ACC DA. Magnitude of 2-Me-5-HT-induced DA release was significantly higher in alcohol-treated rats than in controls. On the other hand, 40 mM K⁺- and 100 mM EtOH-induced extracellular 5-HT release in alcohol-treated rats were markedly inhibited. These results show that (1) chronic alcohol intake increases the sensitivity of 5-HT₃ receptors, (2) 5-HT₃ receptors regulate DA release in the ACC, (3) the dopaminergic neuronal systems associated with 5-HT₃ ionophore in the ACC were upregulated after chronic alcohol exposure, and (4) chronic alcohol intake desensitizes the serotonergic neuronal systems in rat ACC. These findings suggest that neurochemical functions of 5-HT₃ receptors in regulating DA release in the ACC after alcohol exposure compensate for the dysfunction of serotonergic activity to restore the original properties in processing alcohol tolerance and that the development of alcohol dependence may be mediated by ACC 5-HT₃ receptors.     

Mood-Related Drinking Motives Mediate the Familial Association Between Major Depression and Alcohol Dependence

Background:  Major depression and alcohol dependence co-occur within individuals and families to a higher than expected degree. This study investigated whether mood-related drinking motives mediate the association between major depression and alcohol dependence, and what the genetic and environmental bases are for this relationship.
Methods:  The sample included 5,181 individuals from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders, aged 30 and older. Participants completed a clinical interview which assessed lifetime major depression, alcohol dependence, and mood-related drinking motives.
Results:  Mood-related drinking motives significantly explained the depression-alcohol dependence relationship at both the phenotypic and familial levels. Results from twin analyses indicated that for both males and females, the familial factors underlying mood-related drinking motives accounted for virtually all of the familial variance that overlaps between depression and alcohol dependence.
Conclusions:  The results are consistent with an indirect role for mood-related drinking motives in the etiology of depression and alcohol dependence, and suggest that mood-related drinking motives may be a useful index of vulnerability for these conditions.     

Sex Differences in the Sources of Genetic Liability to Alcohol Abuse and Dependence in a Population-Based Sample of U.S. Twins

BACKGROUND: There are substantial sex differences in all levels of alcohol involvement among U.S. adults. The goal of this study was to test whether the magnitude and sources of genetic and environmental influences on liability for alcohol abuse and dependence differ for men and women. METHODS: Structured personal interviews were used to assess DSM-III-R- and DSM-IV-defined alcohol abuse and dependence among 5091 male and 4168 female twins (including 1546 identical, 1128 same-sex fraternal, and 1423 opposite-sex pairs) born in Virginia between 1934 and 1974. Twin correlations were analyzed using structural equation modeling. RESULTS: The magnitude of twin-pair resemblance was similar across several definitions of alcoholism and was substantially higher among identical than fraternal pairs. The proportion of population variation in liability attributed to genetic factors was substantial among both women (55-66%) and men (51-56%), and we found little evidence of a role of environmental factors shared by family members. In all definitions studied, we could reject a model that the genetic sources of liability in the two sexes overlap completely. CONCLUSION: In this first population-based study of alcoholism among male and female twins from the U.S., we found that genetic factors play a major role in the development of alcoholism in both sexes, that the magnitudes of genetic influence were equally high for men and women, and that the genetic sources of vulnerability are partially, but not completely, overlapping in men and women.     

Association of functional opioid receptor genotypes with alcohol dependence in Koreans

BACKGROUND: The functional polymorphism (A118G) of the mu-opioid receptor gene (OPRM1) is thought to have clinical significance in the treatment of alcohol dependence. This study compared Koreans with one or two copies of the A118G polymorphism seeking treatment for alcohol dependence with a group of non-alcohol-dependent controls. METHODS: Patients hospitalized for alcohol dependence (n = 112) and a group of non-alcohol-dependent controls (n = 140) were interviewed on aspects of drinking history and psychiatric history. Patients and controls were excluded if they met criteria for any other major psychiatric disorder. Participants were genotyped at the OPRM1 locus. RESULTS: The allele frequency of the Asp40 allele was 0.397 in the alcohol-dependent group, which is consistent with other literature demonstrating this polymorphism to be common in Asian populations. Within the alcohol-dependent subjects, being homozygous for the Asp40 allele was associated with more days drinking than those heterozygous or homozygous for the Asn40 allele. Differences in the allele frequencies between alcohol-dependent and non-alcohol-dependent controls were not significant. CONCLUSIONS: These results suggest that having one or two copies of the A118G allele is common among Koreans and may be an important genetic factor in the etiology of alcohol dependence and the frequency of alcohol consumption.     

Polymorphisms of the IL-1 Gene Complex Are Associated With Alcohol Dependence in Spanish Caucasians: Data From an Association Study

Background: There is growing evidence for involvement of pro‐inflammatory cytokines in alcohol dependence. The aim of this study was to investigate whether 4 functionally relevant polymorphisms of the interleukin‐1 (IL‐1) and tumor necrosis factor‐alpha genes were associated with alcohol dependence and with measures of clinical severity and treatment outcome. Methods: Two hundred alcohol‐dependent (AD) patients and 420 healthy controls from the same Spanish Caucasian population were genotyped using standard methods. Baseline and 6‐month assessments included alcohol intake, addiction severity, and biomarkers of alcohol intake. Results: Alcohol‐dependent patients showed an excess of IL‐1α?889 C/T [50.8% vs. 39.3%, χ² (df) = 7.30 (2), uncorrected p = 0.026, corrected p = 0.104] and IL‐1RA (86 bp)_n A1/A1 genotypes [64.8% vs. 50.8%, χ² (df) = 12.65 (3), corrected p = 0.020]. The A1/A1 excess was associated with alcohol dependence only in men [69.9% vs. 49.5%, χ² (df) = 15.72 (2), corrected p < 0.001]. Six‐month clinical and hematological outcome measures did not vary by genotype of the 4 polymorphisms. Haplotype analysis revealed an excess of the IL‐1α?889 C/IL‐1β +3953 C/IL‐1RA A2 haplotype in the control group compared with AD patients [20.0% vs. 14.1%, χ² (df) = 7.25 (1), p = 0.007; odds ratio (OR) = 0.64, 95% confidence interval (CI) = 0.46–0.89] and in the abstainers after 6 months of treatment compared with nonabstinent patients [14.7% vs. 6.2%, χ² (df) = 5.65 (1), p = 0.017; OR = 2.56, 95% CI = 1.15–5.62]. Conclusions: Our findings provide further tentative evidence of the role of IL‐1 in alcohol dependence as well as evidence that the nature of the associations may be direct, gender‐specific, or involve haplotype effects. However, findings from single association studies constitute tentative knowledge and must be interpreted carefully and precise replication is required.     

Associations Among GABRG1, Level of Response to Alcohol, and Drinking Behaviors

Background:  Recent studies of the genetics of alcoholism have focused on a cluster of genes encoding for γ-aminobutyric acid (GABA_A) receptor subunits, which is thought to play a role in the expression of addiction phenotypes. This study examined allelic associations between 2 single nucleotide polymorphisms (SNPs) of the GABRG1 gene (rs1391166 and rs1497571) and alcohol phenotypes, namely level of response to alcohol, alcohol use patterns, and alcohol-related problems.
Method:  Participants were non-treatment-seeking seeking hazardous drinkers ( n  = 124) who provided DNA samples, participated in a face-to-face interview for level of response to alcohol, and completed a series of drinking and individual differences measures.
Results:  Analyses revealed that a SNP of the GABRG1 gene (rs1497571) was associated with level of response to alcohol and drinking patterns in this subclinical sample. Follow-up mediational analyses were also conducted to examine putative mechanisms underlying these associations.
Discussion:  These findings replicate and extend recent research suggesting that genetic variation at the GABRG1 locus may underlie the expression of alcohol phenotypes, including level of response to alcohol.     

MAOA Interacts With the ALDH2 Gene in Anxiety–Depression Alcohol Dependence

Background: Alcohol dependence is usually comorbid with anxiety disorder, depressive disorder, or both; this comorbidity may increase drinking behavior. We previously hypothesized that anxiety–depressive alcohol dependence (ANX/DEP ALC) was a genetically specific subtype of alcohol dependence. ANX/DEP ALC may be related to dopamine and serotonin, which are catalyzed by monoamine oxidase A (MAOA) and acetaldehyde dehydrogenase 2 (ALDH2). The aim of this study was to determine whether the interaction between the MAOA and the ALDH2 genes is associated with ANX/DEP ALC. Methods: We recruited 383 Han Chinese men in Taiwan: 143 ANX/DEP ALC and 240 healthy controls. The diagnosis of ANX/DEP ALC (alcohol dependence with a past or current history of anxiety, depressive disorder, or both) was made using DSM‐IV criteria. Genotypes of ALDH2 and MAOA‐uVNTR (variable number of tandem repeat located upstream) were determined using PCR‐RFLP. Results: The ALDH2, but not the MAOA‐uVNTR, polymorphism was associated with ANX/DEP ALC. After stratifying the MAOA‐uVNTR polymorphism, we found a stronger association between the ALDH2*1/*2 and *2/*2 genotypes and the controls in the MAOA‐uVNTR 4‐repeat subgroup. Logistic regression significantly associated the interaction between ALDH2 and MAOA variants with ANX/DEP ALC. Conclusion: We conclude that the MAOA and ALDH2 genes interact in ANX/DEP ALC. Although the MAOA gene alone is not associated with ANX/DEP ALC, we hypothesize that different variants of MAOA‐uVNTR polymorphisms modify the protective effects of the ALDH2*2 allele on ANX/DEP ALC in Han Chinese in Taiwan.