Drug-related phenotypes are common complex and highly heritable traits. In the last few years, candidate gene (CGAS) and genome-wide association studies (GWAS) have identified a huge number of single nucleotide polymorphisms (SNPs) associated with drug use, abuse or dependence, mainly related to alcohol or nicotine. Nevertheless, few of these associations have been replicated in independent studies. The aim of this study was to provide a review of the SNPs that have been most significantly associated with alcohol-, nicotine-, cannabis- and cocaine-related phenotypes in humans between the years of 2000 and 2012. To this end, we selected CGAS, GWAS, family-based association and case-only studies published in peer-reviewed international scientific journals (using the PubMed/MEDLINE and Addiction GWAS Resource databases) in which a significant association was reported. A total of 371 studies fit the search criteria. We then filtered SNPs with at least one replication study and performed meta-analysis of the significance of the associations. SNPs in the alcohol metabolizing genes, in the cholinergic gene cluster CHRNA5-CHRNA3-CHRNB4, and in the DRD2 and ANNK1 genes, are, to date, the most replicated and significant gene variants associated with alcohol- and nicotine-related phenotypes. In the case of cannabis and cocaine, a far fewer number of studies and replications have been reported, indicating either a need for further investigation or that the genetics of cannabis/cocaine addiction are more elusive. This review brings a global state-of-the-art vision of the behavioral genetics of addiction and collaborates on formulation of new hypothesis to guide future work.

The cannabinoid receptor (CNR1) and the fatty acid amide hydrolase (FAAH) genes are located on chromosomes 6 and 1 in the 6q15 and 1p33 cytogenetic bands, respectively. CNR1 encodes a seven-transmembrane domain protein of 472 amino acids, whereas FAAH encodes one transmembrane domain of 579 amino acids. Several mutations found in these genes lead to altered mRNA stability and transcription rate or a reduction of the activity of the encoded protein. Increasing evidence shows that these functional mutations are related to dependence upon cocaine, alcohol, marijuana, heroin, nicotine and other drugs. One of the most compelling associations is with the C385A single nucleotide polymorphism (SNP), which is found in the FAAH gene. For all of the genetic polymorphisms reviewed here, it is difficult to form overall conclusions due to the high diversity of population samples being studied, ethnicity, the use of volunteers, heterogeneity of the recruitment criteria and the drug addiction phenotype studied. Care should be taken when generalizing the results from different studies. However, many works have repeatedly associated polymorphisms in the CNR1 and FAAH genes with drug-related behaviours; this suggests that these genes should be examined in further genetic studies focusing on drug addiction and other psychiatric disorders.

Drug addiction is a complex disease with overlapping stages and influenced by multiple environmental and genetic factors. In addition to neurobiological changes, repeated drug exposure modulates affective responses to drug stimuli including visual cues. Here, we made a preliminary screening among ten Single Nucleotide Polymorphisms (SNP) of the CNR1 (rs806368, rs1049353, rs6454674, rs7766029), FAAH (rs324420, rs12075550), DRD2 (rs6277), ANKK1 (rs1800497), COMT (rs4680), and OPRM1 (rs1799971) genes to identify that SNPs that were more directly associated with alcohol, tobacco and/or cannabis consumption in young individuals (n = 91). Also, affective rating for alcohol-, tobacco- and cannabis-related pictures was examined in each individual. Our results make it possible to select the rs324420 SNP (C385A) of the FAAH gene for further analysis. Increasing the sample size up to n = 185 we found that the homozygous CC C385A SNP genotype was associated with risky alcohol use (p = 0.006, odds ratio 2.38). Subsequently, we replicated this genetic association with risky alcohol use using another independent sample. Risky drinkers (mean 166.8 g pure alcohol) and smokers (more than 15 cigarettes) rated drug pictures more positively (p < 0.001) and they showed a strong positive correlation with drug use during weekends, which is the period in which the first problematic experiences with alcohol and other drugs appear (initial stages of the drug addiction process). As conclusion, because drug addiction is a multi-step process and a preventable disease, our results indicate that the FAAH C385A SNP is one of the most promising candidates for individuals who are at higher risk for alcohol problems.

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Our results suggest that increases in HDAC gene expression within the peripheral blood are associated with chronic alcohol consumption, whereas HDAC gene expression is reduced following initial exposure to alcohol.