OPRM1 A118G Research Articles

OPRM1 rs1799971 Polymorphism and Opioid Dependence: Evidence from a Meta-Analysis

The OPRM1 gene encodes the µ-opioid receptor, which is the primary site of action of most opioids. Several studies and three meta-analyses have examined a possible link between the exonic OPRM1 A118G (rs1799971) polymorphism and opioid dependence; however, results have been inconclusive. Therefore, a systematic review and meta-analysis have been carried out to examine whether this polymorphism is associated with opioid dependence. Thirteen studies (n = 9385), comprising 4601 opioid dependents and 4784 controls, which evaluated association of the OPRM1 rs1799971 polymorphism with susceptibility to opioids, were included in this study. Our meta-analysis showed significant association between this polymorphism and susceptibility to opioid dependence in overall studies under a codominant model, as well as susceptibility to opioid dependence or heroin dependence in Asians under an autosomal dominant model. The nonsynonymous OPRM1 rs1799971 might be a risk factor for addiction to opioids or heroin in an Asian population.

Likely linkage: genetic variations in the mesolimbic dopamine system and elevated risk of opioid abuse in chronic pain patients

Chronic pain patients taking narcotic pain medications were evaluated for the prevalence of genotypes linked with neurochemical deficiencies. They were genotyped using proprietary Proove Narcotic Risk Using Applied Biosystems RealTime PCR TaqMan assay on DRD1-48A>G, DRD2 A1 allele, DRD4-521C/T, DAT1 Ddel, COMT Val158Met, OPRK1 36G>T, OPRM1 A1 18G, DBH-1021C/T, 5-HT2A-1438G/A, 5-HTTLPR, GABA 1519T>C and MTHFR C677T. Subjects were chronic pain patients taking Rx narcotics (n=100). Statistical significance was found in the prevalence of DRD4-521C/T[79% v 29%](p<0.001), DAT1 Ddel[68% v 55%](p<0.05), COMT Val158met[74% v 47%](p<0.001), OPRK1 36G>T[16% v 3%](p<0.05) and OPRM1 A1 18G[17% v 47%](p<0.01). The prevalence of genetic predisposition to substance abuse among chronic pain patients taking prescription narcotic pain medications provides information to prescribers that may improve therapeutic decisions to avoid treatment failures and addiction. This study was supported by Proove Biosciences Inc.

Among women with substantial peritraumatic distress after minor motor vehicle collision (MVC), the presence of one or more G alleles at OPRM1 A118G is protective against developing persistent moderate or severe pain

Among women with substantial peritraumatic distress after minor motor vehicle collision (MVC), the presence of one or more G alleles at OPRM1 A118G is protective against developing persistent moderate or severe pain

Genotyping the Mu‐Opioid Receptor A118G Polymorphism Using the Real‐time Amplification Refractory Mutation System: Allele Frequency Distribution Among Brazilians

The mu-opioid receptor (OPRM1) A118G polymorphism has been associated with decreased analgesic effects of opioids and predisposition to addiction. However, its role in specific clinical scenarios and in different ethnicities must be better defined. No studies evaluating the A118G polymorphism in the Brazilian population have yet been published. Genomic DNA was isolated from peripheral leukocytes of 200 surgical patients of the Center-West region of Brazil. Our genotyping protocol was developed based on the real-time amplification refractory mutation system and validated by comparison with cycle sequencing. Functional consequences of the A118G polymorphism were studied by comparing tobacco smoking prevalence and exposure between genotype groups. We observed perfect correlation between genotyping and sequencing results. Frequency of the G allele was 16% (IC 95% 12.7-19.9%) in our sample. Genotype distribution revealed 146 (73%) patients 118A homozygous, 44 (22%) heterozygous, and 10 (5%) homozygous for the G variant. After grouping patients according to the presence of the G allele, we did not observe differences in smoking prevalence; however, patients with one or two copies of the 118G allele reported higher tobacco exposure than patients 118A homozygous measured in pack-years (28.9±12.5 vs. 21.5±10.8, respectively, P=0.02). We developed a fast and reliable genotyping method to identify the allele frequency distribution of the OPRM1 A118G polymorphism among patients from Center-West Brazil. Our preliminary results suggest functional consequences of the polymorphism on smoking behavior among Brazilians.

The correlation between post-operative fentanyl requirements and μ-opioid receptor gene A118G polymorphism in patients undergoing radical gastrectomy

The aim of this study was to investigate the effect of the μ-opioid receptor gene (OPRM1) A118G polymorphism on the requirement for post-operative fentanyl analgesia in patients undergoing radical gastrectomy. One hundred and twenty-eight gastric cancer patients scheduled to undergo radical gastrectomy under general anesthesia were enrolled in the study. Post-operative, patient-controlled intravenous analgesia of fentanyl was provided for satisfactory analgesia until 48 h after surgery. OPRM1 A118G was screened by DNA sequence analysis of polymerase chain reaction (PCR)-amplified DNA. Differences in fentanyl consumption and adverse effects were compared among the different genotypes at 24 and 48 h after surgery. The ranges of fentanyl dose in the 128 patients at 24 and 48 h after surgery were 5.4–17.3 μg/kg and 12.4–29.9 μg/kg, respectively. Among these patients, there were 54 wild-type homozygotes (AA), 53 heterozygotes (AG) and 21 mutant homozygotes (GG). The frequency of the G allele was 0.371 in the OPRM1 polymorphism. There were no significant differences in fentanyl dose or adverse effects, including nausea, vomiting and dizziness, for the OPRM1 A118G polymorphism (P>0.05). The OPRM1 A118G polymorphism does not play a significant role in post-operative fentanyl analgesic dose or post-operative nausea, vomiting and dizziness in patients undergoing radical gastrectomy.

Effect of CYP3A4*18B polymorphisms and interactions with OPRM1 A118G on postoperative fentanyl requirements in patients undergoing radical gastrectomy

The present study aimed to investigate the effect of cytochrome P450 3A4 (CYP3A4)*18B polymorphisms and the interaction of the µ opioid receptor gene (OPRM1) A118G and CYP3A4*18B polymorphisms on postoperative fentanyl analgesia in Chinese Han patients undergoing radical gastrectomy. In total, 97 patients scheduled to undergo radical gastrectomy under general anesthesia were enrolled in this study. Post‑operative patient‑controlled intravenous analgesia of fentanyl was administered as analgesia up to 48h following surgery. Venous blood (2ml) was obtained from each patient to measure the OPRM1 A118G and CYP3A4*18B genotypes. The differences in fentanyl consumption and adverse effects were compared among the genotypes at 24 and 48h following surgery. In the first 48h following surgery, patients in the CYP3A4*18B/*18B group consumed significantly less fentanyl compared with patients in the *1/*1 group (P=0.032). With regards to the joint genetic effect, during the 48‑h period, patients with AA and *1*18B polymorphisms received fewer fentanyl doses compared with those with AG and *1*1 (P=0.049), while patients with AG and *1*18B polymorphisms received significantly fewer fentanyl doses compared with those with AG and *1*1 (P=0.010), and patients with *18B*18B polymorphisms received significantly fewer fentanyl doses compared with those with AA and *1*1 (P=0.024) or those with AG and *1*1 polymorphisms (P=0.006). No correlation between OPRM1 A118G and CYP3A4*18B and postoperative nausea, vomiting and dizziness was found. Results demonstrated that 48h following surgery, patients with the CYP3A4*18B/*18B genotype required less fentanyl than patients with the CYP3A4*1/*1 genotype to control pain. Additionally, the combined genotype of CYP3A4*18B and OPRM1 A118G may affect fentanyl doses administered for pain control, but not postoperative nausea, vomiting and dizziness.

The human μ-opioid receptor gene polymorphism (A118G) is associated with head pain severity in a clinical cohort of female migraine with aura patients

Migraine is a painful and debilitating, neurovascular disease. Current migraine head pain treatments work with differing efficacies in migraineurs. The opioid system plays an important role in diverse biological functions including analgesia, drug response and pain reduction. The A118G single nucleotide polymorphism (SNP) in exon 1 of the μ-opioid receptor gene (OPRM1) has been associated with elevated pain responses and decreased pain threshold in a variety of populations. The aim of the current preliminary study was to test whether genotypes of the OPRM1 A118G SNP are associated with head pain severity in a clinical cohort of female migraineurs. This was a preliminary study to determine whether genotypes of the OPRM1 A118G SNP are associated with head pain severity in a clinical cohort of female migraineurs. A total of 153 chronic migraine with aura sufferers were assessed for migraine head pain using the Migraine Disability Assessment Score instrument and classified into high and low pain severity groups. DNA was extracted and genotypes obtained for the A118G SNP. Logistic regression analysis adjusting for age effects showed the A118G SNP of the OPRM1 gene to be significantly associated with migraine pain severity in the test population (P = 0.0037). In particular, G118 allele carriers were more likely to be high pain sufferers compared to homozygous carriers of the A118 allele (OR = 3.125, 95 % CI = 1.41, 6.93, P = 0.0037). These findings suggest that A118G genotypes of the OPRM1 gene may influence migraine-associated head pain in females. Further investigations are required to fully understand the effect of this gene variant on migraine head pain including studies in males and in different migraine subtypes, as well as in response to head pain medication.

The Associations Between OPRM1 and COMT Genotypes and Postoperative Pain, Opioid Use, and Opioid-Induced Sedation

Previous studies have associated mu-opioid receptor (OPRM1) genotype with pain and analgesia responses in postoperative and patient populations. This study investigates the role of catechol-O-methyltransferase (COMT) and OPRM1 genotypes in acute postoperative pain scores, opioid use, and opioid-induced sedation after surgical procedures for orthopedic trauma in an otherwise healthy patient population. Verbal pain/sedation scores, opioid use, and physiologic responses in the immediate postoperative period were examined for association with genetic variants in Caucasians genotyped for OPRM1 single nucleotide polymorphisms (SNPs) A118G and C17T and COMT SNPs. The OPRM1 A118G genotype was associated with patients' postoperative Numerical Pain scale (NPS) ratings at 15 min in the postanesthesia care unit (PACU) (p = .01) and patients' sedation scores at 15 min in the PACU (p = .02). COMT genotype (rs4818) was associated with opioid consumption in the first 45 min in the PACU (p = .04). NPS ratings at 45 min were also higher in the group of patients with A/A genotype of rs4680 than in patients with the other two genotypes at this SNP (p = .03). Our haplotype trend analysis identified a COMT haplotype "GCGG" significantly associated with NPS at 15 min (p = .0013), amount of opioids consumed in the first 45 min (p = .0024), and heart rate at 45 min in the PACU (p = .017). The results indicate that genetic variations in COMT contribute to the acute postoperative pain and analgesia responses and physiologic responses in this group of otherwise healthy postoperative orthopedic trauma patients.

Genotypic screening of the main opiate‐related polymorphisms in a cohort of 139 sickle cell disease patients

Because no frequency data are available for the main opiate-related polymorphisms in sickle-cell disease (SCD) populations, we decided to perform such a genotyping in a cohort of 139 individuals. For pharmacodynamics,the OPRM1 A118G and the COMT G322A single nucleotide polymorphisms (SNPs) were chosen for their negative effects on the m receptors [1,2]. For pharmacokinetics [3], important SNPs for the CYP2D6 gene (codeine to morphine conversion) and for three genes involved in morphine elimination (namely CYP3A, UGT2B7, and ABCB1) were genotyped. The allelic frequencies of the OPRM1 and COMT SNPs appeared very low (0.01 to 0.05-no double mutant homozygous),as well as the proportion of CYP2D6 poor metabolizers (1.4%)and CYP3A wild-type (17.9%) which are associated with a low morphine exposure. On the contrary, up to 35% of SCD patients may have unfavorable ABCB1 and UGT2B7 genotypes for a good morphine exposure.Obviously, pharmacokinetic studies with precise phenotype/genotype correlations are required to draw definitive conclusions.

Reduced expression of the mu opioid receptor in some, but not all, brain regions in mice with OPRM1 A112G

OPRM1 A118G is a common single nucleotide polymorphism (SNP) in the coding region of the human mu opioid receptor (MOPR) gene OPRM1. This SNP is associated with higher morphine doses required for postoperative analgesia as well as a variety of drug addiction phenotypes. A mouse model possessing the equivalent substitution (A112G) in the Oprm1 gene was generated to facilitate mechanistic studies. Mice homozygous for the G112 allele (G/G) displayed lower antinociception to morphine compared with those homozygous for A112 allele (A/A), similar to humans, suggesting that the mice are a good model to further characterize underlying factors contributing to phenotypes associated with this SNP. Here, we compared [3H]DAMGO binding to the MOPR in the brains of A/A and G/G mice using quantitative in vitro autoradiography. A/A mice exhibited higher [3H]DAMGO binding than G/G in the cingulate, motor, and insular cortices, nucleus accumbens core and shell, hypothalamus, thalamus, amygdala, periaqueductal gray, superficial gray of superior colliculus, and ventral tegmental area. No genotype differences were observed in somatosensory cortex, caudate putamen, and hippocampus. When males and females were examined separately, A/A mice showed higher [3H]DAMGO binding than G/G mice in more brain regions in males than in females. Radioligand binding using brain membranes also showed higher [3H]DAMGO binding in the cortex and thalamus in A/A mice than G/G mice but no genotype differences in the caudate putamen or hippocampus. Thus, the A112G SNP is associated with reduced MOPR expression in some, but not all, brain regions, and appears to have some sex differences. The elevated MOPR expression in periaqueductal gray and thalamus in A/A mice are consistent with their higher antinociceptive responses to morphine. The higher MOPR levels in nucleus accumbens and/or ventral tegmental area of A/A mice is consistent with the higher morphine-induced hyperactivity and locomotor sensitization observed in these mice. Thus, these results provide some insights into the observed decreased clinical opioid potency in humans with the A118G SNP.

OPRM1 A118G genotype fails to predict the effectiveness of naltrexone treatment for alcohol dependence

Given the evidence from retrospective studies indicating that alcohol-dependent patients with homozygous or heterozygous A118G variant of the μ-opioid receptor, OPRM1, gene have significantly better outcomes when treated with naltrexone; this study examined this prospectively in 100 alcohol-dependent participants prescribed naltrexone for 12 weeks and offered six sessions of cognitive-behavioral therapy or intervention. Comparisons were made among OPRM1 genotypic groups on several outcome measures. Naltrexone treatment produced significant decreases in self-reported and objective indicators of alcohol use and craving from baseline (P<0.0001 and 0.017, respectively), particularly during the first 2 months of treatment, with 68% completing the study. However, there was no evidence of a significant association between OPRM1 A118G genotype and treatment success on any of the outcome measures. Therefore, while naltrexone was an effective treatment for alcohol dependence, the OPRM1 A118G genotype was not a predictor of success.

Functional polymorphism of the mu-opioid receptor gene (OPRM1) influences reinforcement learning in humans.

Previous reports on the functional effects (i.e., gain or loss of function), and phenotypic outcomes (e.g., changes in addiction vulnerability and stress response) of a commonly occurring functional single nucleotide polymorphism (SNP) of the mu-opioid receptor (OPRM1 A118G) have been inconsistent. Here we examine the effect of this polymorphism on implicit reward learning. We used a probabilistic signal detection task to determine whether this polymorphism impacts response bias to monetary reward in 63 healthy adult subjects: 51 AA homozygotes and 12 G allele carriers. OPRM1 AA homozygotes exhibited typical responding to the rewarded response—that is, their bias to the rewarded stimulus increased over time. However, OPRM1 G allele carriers exhibited a decline in response to the rewarded stimulus compared to the AA homozygotes. These results extend previous reports on the heritability of performance on this task by implicating a specific polymorphism. Through comparison with other studies using this task, we suggest a possible mechanism by which the OPRM1 polymorphism may confer reduced response to natural reward through a dopamine-mediated decrease during positive reinforcement learning.

Interindividual Variability in the Prevalence of OPRM1 and CYP2B6 Gene Variations May Identify Drug-Susceptible Populations

Methadone is used worldwide for the treatment of heroin addiction; however, fatal poisonings are increasingly reported. The prevalence of CYP2B6 and μ-opioid receptor (OPRM1) gene variations were examined between a postmortem population where the deaths were associated with methadone and a live nondrug-using control population using Taqman™ SNP Genotyping assays. The CYP2B6*6 allele was higher in the postmortem population, but the difference was not significant (P = 0.92). The CYP2B6 T750C promoter variation was similar in frequency for both populations. Linkage between T750C and CYP2B6*6 was identified for both populations (P < 0.01). The prevalence of the OPRM1 A118G variation was significantly higher in the control population (P = 0.0046), which might indicate a protective mechanism against opioid toxicity. Individual susceptibility to methadone may be determined by screening for CYP2B6*6.

Human mu‐opioid receptor gene A118G polymorphism predicts the efficacy of tramadol/acetaminophen combination tablets (ultracet) in oxaliplatin‐induced painful neuropathy

The A118G polymorphism of the mu-opioid receptor gene (OPRM1), resulting in the substitution of an amino acid, has been found to be associated with functional effects and response to opioid treatment. The purpose of this study was to assess whether this polymorphism contributes to the variability in response to tramadol/acetaminophen combination tablets (Ultracet) for treating oxaliplatin-induced painful neuropathy. A total of 96 patients with adenocarcinoma of the colon or rectum (n = 84), or stomach (n = 12) who had developed oxaliplatin-induced painful neuropathy were enrolled. Ultracet was administered at 1 tablet every 6 hours, and pain was assessed and scored using a visual analog scale (VAS). The OPRM1 A118G polymorphism was examined with a polymerase chain reaction-direct sequencing method. The allelic frequency of variant (118G) allele was 39.6%, and the prevalence of OPRM1-118 AA, AG, and GG genotypes was 31.3% (n = 30), 58.3% (n = 56), and 10.4% (n = 10), respectively. For all patients, the mean pre-treatment and post-treatment VAS scores were 3.1 and 2.1, respectively (P < .001). Patients with AA genotype had a better analgesic effect than those with G allele variants (AG or GG genotypes). Pre-treatment and post-treatment VAS scores for patients with G allele variants were 3.1 and 2.6, respectively; however, for patients with AA genotype, pre-treatment and post-treatment VAS scores were 3.0 and 0.9, respectively (P < .001). The requirement for rescue analgesia was also higher for patients with G allele variants (P = .01). These data suggest that Ultracet is effective in the management of oxaliplatin-induced painful neuropathy. A118G polymorphism of OPRM1, by altered function of the mu-opioid receptor and consequential analgesic effect on opioid agents, could be a key determinant for decreased response to Ultracet.

OPRM1 gene variation influences hypothalamic–pituitary–adrenal axis function in response to a variety of stressors in rhesus macaques

The endogenous opioid system is involved in modulating a number of behavioral and physiological systems, including the hypothalamic-pituitary-adrenal (HPA) axis. In humans, a functional variant in the OPRM1 gene (OPRM1 A118G) is associated with a number of outcomes, including attenuated HPA axis responses to stress. A nonsynonymous variant (OPRM1 C77G) in the rhesus macaque has been shown to have similar effects in vivo to the human variant. The current study investigated whether OPRM1 C77G influences HPA axis response to stress in rhesus macaques. We analyzed plasma adrenocorticotropic hormone (ACTH) and cortisol levels measured in response to three different stressors: (1) maternal separation in infant subjects at 6 months of age, (2) acute ethanol administration in adolescent subjects at 4 years of age, and (3) postpartum HPA axis function in adult rhesus macaque females. For the maternal separation paradigm, ACTH and cortisol levels were determined at baseline as well as peak levels during each of 4 consecutive separation episodes. For the acute ethanol administration paradigm, hormone levels were determined at baseline and again at 5 min, 10 min, and 60 min following the ethanol infusion. For postpartum sampling, hormone levels were determined at postpartum days 7, 14, 21, 30, 60, 90, 120, and 150. Infants carrying the 77G allele exhibited lower levels of cortisol across all 4 separation episodes. Furthermore, adolescents carrying the 77G allele exhibited lower cortisol levels at 5 and 10 min following acute ethanol administration. Adult females with prior reproductive experience and who carry the 77G allele exhibited lower cortisol levels across the postpartum period. No significant genotype effects were found for ACTH, although there were some trends for lower ACTH levels in 77G allele carriers. These data are consistent with human studies that have demonstrated attenuated cortisol responses to stress among carriers of the OPRM1 118G allele, lending further support to the argument that the rhesus and human allelic variants are functionally similar. Our results also suggest that OPRM1 variation may influence coping style, as well as alcohol-induced and postpartum levels of HPA axis activity and, as such, may modify vulnerability to alcohol use disorders and postpartum depression.

Child μ-Opioid Receptor Gene Variant Influences Parent–Child Relations

Variation in the μ-opioid receptor gene has been associated with early social behavior in mice and rhesus macaques. The current study tested whether the functional OPRM1 A118G predicted various indices of social relations in children. The sample included 226 subjects of self-reported European ancestry (44% female; mean age 13.6, SD=2.2) who were part of a larger representative study of children aged 9-17 years in rural North Carolina. Multiple aspects of recent (past 3 months) parent-child relationship were assessed using the Child and Adolescent Psychiatric Assessment. Parent problems were coded based upon a lifetime history of mental health problems, substance abuse, or criminality. Child genotype interacted with parent behavior such that there were no genotype differences for those with low levels of parent problems; however, when a history of parent problems was reported, the G allele carriers had more enjoyment of parent-child interactions (mean ratio (MR)=3.5, 95% CI=1.6, 8.0) and fewer arguments (MR=3.1, 95% CI=1.1, 8.9). These findings suggest a role for the OPRM1 gene in the genetic architecture of social relations in humans. In summary, a variant in the μ-opioid receptor gene (118G) was associated with improved parent-child relations, but only in the context of a significant disruption in parental functioning.

CYP2B6 and OPRM1 gene variations predict methadone-related deaths

The largest proportion of methadone-associated deaths occurs during the drug induction phase. We analysed methadone-related fatalities for gene variations linked with methadone action. A significant association between high methadone concentrations and the CYP2B6*6 allele characteristic of the slow metabolizer phenotype was identified. We suggest that the risk of methadone fatality may be predetermined in part by the CYP2B6*6 allele. A significant correlation was also observed between post-mortem benzodiazepine concentrations and the OPRM1 A118G allele GA in methadone-related fatalities. Screening for these susceptibility variations prior to methadone prescription could assist in reducing the potential for serious adverse effects.

OPRM1 and CYP2B6 Gene Variants as Risk Factors in Methadone-Related Deaths

Methadone is a medication valued for its effectiveness in the treatment of heroin addiction; however, many fatal poisonings associated with its use have been reported over the years. We have examined the association between CYP2B6 and micro-opioid receptor (OPRM1) gene variations and apparent susceptibility to methadone poisoning. Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning. The presence of CYP2B6*4,*9, and *6 alleles and the OPRM1 A118G variant was determined by SNP genotyping. CYP2B6 *4, *9, and *6 alleles were found to be associated with higher postmortem methadone concentrations in blood (P < or = 0.05). OPRM1 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance (P = 0.39). In these methadone-related deaths, OPRM1 118GA was associated with higher postmortem benzodiazepine concentrations (P = 0.04), a finding not associated with morphine-related deaths. The risk of a methadone-related fatality during treatment may be evaluated in part by screening for CYP2B6*6 and A118G.

Is there a genetic contribution to cultural differences? Collectivism, individualism and genetic markers of social sensitivity.

Genes and culture are often thought of as opposite ends of the nature-nurture spectrum, but here we examine possible interactions. Genetic association studies suggest that variation within the genes of central neurotransmitter systems, particularly the serotonin (5-HTTLPR, MAOA-uVNTR) and opioid (OPRM1 A118G), are associated with individual differences in social sensitivity, which reflects the degree of emotional responsivity to social events and experiences. Here, we review recent work that has demonstrated a robust cross-national correlation between the relative frequency of variants in these genes and the relative degree of individualism-collectivism in each population, suggesting that collectivism may have developed and persisted in populations with a high proportion of putative social sensitivity alleles because it was more compatible with such groups. Consistent with this notion, there was a correlation between the relative proportion of these alleles and lifetime prevalence of major depression across nations. The relationship between allele frequency and depression was partially mediated by individualism-collectivism, suggesting that reduced levels of depression in populations with a high proportion of social sensitivity alleles is due to greater collectivism. These results indicate that genetic variation may interact with ecological and social factors to influence psychocultural differences.

A genetic determinant of the striatal dopamine response to alcohol in men

Excessive alcohol use, a major cause of morbidity and mortality, is less well understood than other addictive disorders. Dopamine release in ventral striatum is a common element of drug reward, but alcohol has an unusually complex pharmacology, and humans vary greatly in their alcohol responses. This variation is related to genetic susceptibility for alcoholism, which contributes more than half of alcoholism risk. Here, we report that a functional OPRM1 A118G polymorphism is a major determinant of striatal dopamine responses to alcohol. Social drinkers recruited based on OPRM1 genotype were challenged in separate sessions with alcohol and placebo under pharmacokinetically controlled conditions, and examined for striatal dopamine release using positron emission tomography and [11C]-raclopride displacement. A striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. To directly establish the causal role of OPRM1 A118G variation, we generated two humanized mouse lines, carrying the respective human sequence variant. Brain microdialysis showed a four-fold greater peak dopamine response to an alcohol challenge in h/mOPRM1-118GG than in h/mOPRM1-118AA mice. OPRM1 A118G variation is a genetic determinant of dopamine responses to alcohol, a mechanism by which it likely modulates alcohol reward.