Genetic studies of alcohol dependence in the context of the addiction cycle

Abstract

Family, twin and adoption studies demonstrate clearly that alcohol dependence and alcohol use disorders are phenotypically complex and heritable. The heritability of alcohol use disorders is estimated at approximately 50-60% of the total phenotypic variability. Vulnerability to alcohol use disorders can be due to multiple genetic or environmental factors or their interaction which gives rise to extensive and daunting heterogeneity. This heterogeneity makes it a significant challenge in mapping and identifying the specific genes that influence alcohol use disorders. Genetic linkage and (candidate gene) association studies have been used now for decades to map and characterize genomic loci and genes that underlie the genetic vulnerability to alcohol use disorders. These approaches have been moderately successful in identifying several genes that contribute to the complexity of alcohol use disorders. Recently, genome-wide association studies have become one of the major tools for identifying genes for alcohol use disorders by examining correlations between millions of common single-nucleotide polymorphisms with diagnosis status. Genome-wide association studies are just beginning to uncover novel biology; however, the functional significance of results remains a matter of extensive debate and uncertainty. In this review, we present a select group of genome-wide association studies of alcohol dependence, as one example of a way to generate functional hypotheses, within the addiction cycle framework. This analysis may provide novel directions for validating the functional significance of alcohol dependence candidate genes. This article is part of the Special Issue entitled "Alcoholism".

Keywords: Addiction cycle; Alcohol dependence; Alcohol use disorder; Genetic mapping; Genetics; Genome-wide association study.

Fig. 1.

Candidate genes for alcohol dependence characterized into stages of the addiction cycle. This schematic shows the three stages of the addiction cycle: (1): binge-intoxication (blue), (2): withdrawal-negative affect (red) and (3): preoccupation-anticipation (green); also shown are behavioral domains linked to each stage of the cycle: incentive salience, negative emotionality, and executive function, respectively. Candidate functional genes identified by non-GWAS approaches are shown in ovals and colored coded according to the relevant addiction stage the gene is hypothesized to function. GWAS candidates are shown in rectangles color coded according to the relevant addiction stage the gene is hypothesized to function. The general biological function of each gene in the figure is highlighted in black. Non-GWAS functional gene relationships are indicated by overlapping ovals. Hypothesized functional relationships between non-GWAS genes and GWAS candidates are indicated by overlapping ovals and rectangles. GWAS candidates in each stage are grouped according to potential biological functional similarities where possible. Finally, one example of pleiotropy is shown in the preoccupation-anticipation stage. BDNF-COMT functional variants have pleiotropic effects in both the preoccupation-anticipation stage and the withdrawal-negative affect stage. This pleiotropic relationship is shown by dual-color shading of the BDNF-COMT ovals reflecting both addiction stages.