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Lack of associations of the opioid receptor mu 1 (OPRM1) A118G polymorphism (rs1799971) with alcohol dependence: review and meta-analysis of retrospective controlled studies
BMC Medical Genetics volume 18, Article number: 120 (2017)
Studies have sought associations of the opioid receptor mu 1 (OPRM1) A118G polymorphism (rs1799971) with alcohol-dependence, but findings are inconsistent. We summarize the information as to associations of rs1799971 (A > G) and the alcohol-dependence.
Systematically, we reviewed related literatures using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Embase, PubMed, Web of Knowledge, and Chinese National Knowledge Infrastructure (CNKI) databases were searched using select medical subject heading (MeSH) terms to identify all researches focusing on the present topic up to September 2016. Odds ratios (ORs) along with the 95% confidence interval (95% CI) were estimated in allele model, homozygote model, heterozygote model, dominant model and recessive model. Ethnicity-specific subgroup-analysis, sensitivity analysis, heterogeneity description, and publication-bias assessment were also analyzed.
There were 17 studies, including 9613 patients in the present meta-analysis. The ORs in the 5 genetic-models were 1.037 (95% CI: 0.890, 1.210; p = 0.64), 1.074 (95% CI: 0.831, 1.387; p = 0.586), 1.155 (95% CI: 0.935, 1.427; p = 0.181), 1.261 (95% CI: 1.008, 1.578; p = 0.042), 0.968 (95% CI: 0.758, 1.236; p = 0.793), respectively. An association is significant in the dominant model, but there is no statistical significance upon ethnicity-specific subgroup analysis.
The rs1799971 (A > G) is not strongly associated with alcohol-dependence. However, there are study heterogeneities and limited sample sizes.
Alcohol-dependence is a common disorder involving psychological and physical alcohol-dependence despite frequent complications . Based on DSM-IV criteria, no less than 3 out of 7 of the following criteria must be met during 12 months for alcohol-dependence: tolerance; use is continued in spite of knowledge of related harms; recreational, occupational or social pursuits are reduced or given up due to alcohol use; time is spent obtaining alcohol or recovering from effects; unsuccessful efforts or persistent desires to cut down on alcohol-use; use for longer periods or in larger amounts than intended; and withdrawal symptoms or clinically defined alcohol withdrawal syndrome . There are around 76 million people suffered from alcohol dependence worldwide, which is one of the leading psychiatric disorders of adult patients . Its etiology is still unclear . There were some studies indicating heritability of this disorder (ranging from 49% to 64%) [5, 6]. Several studies concerning genome-wide or phenome-wide associations of alcohol dependence were listed in Table 1 [5, 7,8,9,10,11]. These researches suggested that genetic factors might influence the patient susceptibility to alcohol dependence.
A relevant neurotransmitter system is related to endogenous opioids pathway . Drinking alcohol can first increase levels of endogenous opioids (e.g. β-endorphin). Opioid reward system in return can elicit seeking additional alcohol. In addition, binding of μ-opioid receptors to β-endorphin could reinforce alcohol-dependence through increasing dopamine expressions at reward-centers  and then affect individual responses to alcohol. Therefore, genetic variations of OPRM1 might have an effect upon the risks of alcohol-dependence . The rs1799971 is in the OPRM1 coding-area . Though lots of researches have sought associations of the OPRM1 A118G- polymorphism with alcohol-dependence, there was no consensuses.  A Swedish group found that the A118G-polymorphism was connected to an 11% risk of alcohol dependence  while Bergen et al. found no significant association.  We were thus prompted to perform a meta-analysis to provide a full picture of current progress on this topic.
Article search and selection criteria
Two investigators searched CNKI, Embase, Web of Knowledge, and PubMed (up to Sep. 2016). Terms included “alcohol or alcoholic” and “rs1799971 or A118G or OPRM1”. Also, related references were scanned. Inclusion criteria and exclusion criteria are shown in Table 2.
We sought these information: authors’ names, publication-year, nation, ethnicity (Asian, Caucasian, or others), genotyping ways, P value for Hardy-Weinberg equilibrium (HWE),total numbers of controls and cases, controls and cases with OPRM1-A118G polymorphism, with A/A, A/G, and G/G genotypes, and control sources (population-based or hospital-based).
Based on the methodological quality scale (see Table 3), 2 investigators estimated the study qualities independently. Disagreements were resolved by discussions. In the methodological quality assessment scale, five items (sample sizes, quality control of genotyping methods, source of controls, case representativeness, and HWEs) were checked. The scores range between 0 and 10, with 10 indicating highest quality.
This analysis was in accord with the PRISMA checklist and guideline. ORs were computed in 3 steps: 1) for given individuals that have “B”, we computed the odds that the same individuals have “A”; 2) for given individuals that do not have “B”, we computed the odds that the same individuals have “A”; and 3) we divided the odds from step 1 by the odds from step 2, getting the ORs. The pooled ORs were estimated and used for comparisons in the 5 genetic models mentioned above. Ethnicity-specific subgroup-analyses were also made. To estimate the heterogeneities, we performed the I2 tests, Labbe plots, and Cochran’s Q-tests (see Table 4). As it seems likely that there are considerable phenotypic variations between populations in the different studies, we did all these analyses using the random-effects model. By contour-enhanced funnel plots and sensitivity-analysis plots (Table 4), we did publication-bias and sensitivity tests.
A value of P < 0.01 was deemed of statistical significance. Statistical-analyses were conducted with Review Manager 5.3 and STATA 13.0.
Search results and study characteristics
Figure 1 shows the processes of the literature-searching. 17 studies with 9613 patients were included. [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31] Nine studies involved Caucasian subjects and were done in the USA, [15, 16, 24, 28, 30] Germany, [19, 22, 27] and Spain  (8026 subjects in total). Eight involved Asian subjects and were done in China, [23, 26, 29, 31] India,  Japan,  and Korea [20, 21] (1587 subjects in total). Fourteen studies were written in English, [15,16,17,18,19,20,21,22,23,24,25, 27, 28, 30] and three were in Chinese. [26, 29, 31] Alcohol dependence was defined by drinking history. Genotyping methods used included direct sequencing, polymerase chain reaction-restricted fragment length polymorphisms (PCR-RFLP), Puregene™ kit or standard phenol-chloroform method, TaqMan assay, and fluorescence resonance energy transfer method. Ten matchings for the controls were population-based, [15, 16, 18, 24,25,26,27,28,29, 31] 3 were hospital-based, [20,21,22] and 4 were mixed. [17, 19, 23, 30] The characteristics and methodological qualities are in Table 5.
Related results are listed in Table 6. The Labbe plots are as Fig. 2a–c. Overall, statistically significant associations of OPRM1-A118G polymorphism with alcohol-dependence was detected only in the dominant model (OR 1.261, 95% CI 1.008, 1.578; p = 0.042; Fig. 6). In the other four models, any associations were not significant (allele model: OR 1.037, 95% CI 0.890, 1.210; p = 0.640; Fig. 3; homozygote model: OR 1.074, 95% CI 0.831, 1.387; p = 0.586; Fig. 4; heterozygote model: OR 1.155, 95% CI 0.935, 1.427; p = 0.181; Fig. 5; recessive model: OR 0.968, 95% CI 0.758, 1.236; p = 0.793; Fig. 7).
The ethnicities are an Asian group and a Caucasian group. The corresponding results are shown in Table 6 and Figs. 3, 4, 5, 6, 7. For both the 2 subgroups, the OPRM1-A118G polymorphism had no association with alcohol-dependence in all these 5 genetic-models.
Sensitivity analysis and publication bias
The ORs were not influenced by removing any single article (Fig. 2d–f). We had searched all possible studies both in Chinese databases and English databases to reduce the publication bias. Contour-enhanced funnel plots demonstrated that the studies only had missing areas for high statistical significance instead of low significance areas, thus very little or none publication bias was detected (Fig. 2g–i).
Alcohol dependence is estimated to exhibit heritability of more than 50% [5, 6], indicating genetic factors might play pivotal roles alcohol-dependence. Genome-wide or phenome-wide associations researches of alcohol-dependence was presented in Table 1. In view of the significances of μ-opioid receptor systems in physiologic mechanisms of reward centers, it is safe to say that OPRM1-polymorphisms had an influence on alcohol-dependence risks. [32, 33] Therefore, we focused our study on OPRM1 A118G, which is a functional allelic-variant with deleterious effects on protein and mRNA expressions. 
Close associations are suspected of the OPRM1 A118G polymorphism (A > G) with nicotine, alcohol, and opioid dependence. [13, 35, 36] Kapur et al. and Tan et al. discovered close associations between A118G-polymorphisms and heroin dependence. [37, 38] Modulation changes of kinase A are likely responsible for the close associations of the OPRM1 A118G polymorphism (A > G) with heroin dependence.  Recently, Frances et al. found that the OPRM1 A118G polymorphism (A > G) was associated with alcohol/tobacco-dependence in a Spanish population, and this association was related to several environmental and genetic factors.  However, the study from Rouvinen-Lagerstrom et al. suggested that the effect of A118G-polymorphism on the development of alcohol dependence was not statistically significant (P > 0.05).  In a study by Franke et al., data from ethnically homogenous samples detected no actual difference of the OPRM1 A118G polymorphism between alcohol dependent subjects and controls. 
We combed PubMed, Embase, Web of knowledge and CNKI databases in search of associations of alcohol dependence with the OPRM1 A118G polymorphism to cover the most information sourced from both Chinese and English studies. In our meta-analysis, significant associations between alcohol-dependence risks and A118G-polymorphisms were only found in the dominant model (OR 1.261, 95% CI 1.008, 1.578; p = 0.042). Association was non-significant in four other models. For subgroup analyses of Caucasian or Asian group each considered separately, the OPRM1 A118G polymorphism did not have association with alcohol dependence in all five genetic models.
In the contour-enhanced funnel plots, each circle represented a study. If studies appeared to be missing in areas of low statistical significance (the left part of the plot), the asymmetry is likely to be due to publication-biases.  In the present study, funnel plots indicated no publication bias.
There are potential limitations in our meta-analysis. The numbers of studies (nine and eight) as well as sample sizes for each ethnicity were limited. Type-II error could not be dismissed.  In addition, effects of gene-environment interactions and gene-gene interactions were not analyzed as not all eligible articles included these type of data. Within those studies with genomic interaction data, confounding factors were controlled and reported differently. Last, ORs adjusted by patient characteristics including genders, ages, living styles, medication-consumptions and other exposure-factors using meta-regression could be calculated with higher accuracy if related data were available in the majority of eligible studies.
The opioid receptor mu 1 (OPRM1) A118G polymorphism (rs1799971) is not associated with alcohol dependence in Caucasian nor Asian populations.
- 95% CI:
95% confidence interval
Chinese National Knowledge Infrastructure
Medical Subject Heading
opioid receptor mu 1
polymerase chain reaction-restricted fragment length polymorphisms.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
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We thank our colleagues at the Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.
This study was supported by China Scholarship Council of the Ministry of Education, P. R. China. This study was funded by Peking Union Medical College Youth Research Funds (2016) (Project No. 3332016010; Grant recipient: Xiangyi Kong). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Kong, X., Deng, H., Gong, S. et al. Lack of associations of the opioid receptor mu 1 (OPRM1) A118G polymorphism (rs1799971) with alcohol dependence: review and meta-analysis of retrospective controlled studies. BMC Med Genet 18, 120 (2017) doi:10.1186/s12881-017-0478-4
- OPRM1 A118G