Recent Efforts to Dissect the Genetic Basis of Alcohol Use and Abuse

Abstract

Alcohol use disorder (AUD) is defined by several symptom criteria, which can be dissected further at the genetic level. Over the past several years, our understanding of the genetic factors influencing alcohol use and abuse has progressed tremendously; numerous loci have been implicated in different aspects of alcohol use. Previously known associations with alcohol-metabolizing enzymes (ADH1B, ALDH2) have been replicated definitively. In addition, novel associations with loci containing the genes KLB, GCKR, CRHR1, and CADM2 have been reported. Downstream analyses have leveraged these genetic findings to reveal important relationships between alcohol use behaviors and both physical and mental health. AUD and aspects of alcohol misuse have been shown to overlap strongly with psychiatric disorders, whereas aspects of alcohol consumption have shown stronger links to metabolism. These results demonstrate that the genetic architecture of alcohol consumption only partially overlaps with the genetics of clinically defined AUD. We discuss the limitations of using quantitative measures of alcohol use as proxy measures for AUD, and we outline how future studies will require careful phenotype harmonization to properly capture the genetic liability to AUD.

Keywords: AUDIT; Alcohol consumption; Alcohol-metabolizing genes; Alcoholism; Genetics; Genome-wide association studies.

Figure 1.

The downward spiral of alcohol use disorders. There is an initial prodromal stage during which certain individuals may be at increased risk to be exposed to alcohol. Personality traits such as sensation seeking are thought to promote alcohol experimentation, and transition to a more regular use of alcohol. As alcohol use patterns become more frequent, and tolerance develops, individuals are more likely to loss control over alcohol drinking behavior; risk factors, such as impulsivity, are considered to promote the transition to a more harmful use of alcohol. Alcohol intake may then become inflexible and compulsive, leading to hazardous or continuous alcohol use despite the negative physical and psychological consequences, and ultimately stagnating into dependence. Attempts to quit or cut-down may become apparent; these may be followed by an aversive negative affective state, or withdrawal, thereby increasing the urges to use alcohol, precipitating relapse, and thus perpetuating the spiral of alcohol use disorders.

Figure 2.

Timeline of major findings in alcohol use behaviors (alcohol use, yellow; alcohol sensitivity and withdrawal, light orange; alcohol misuse, orange; alcohol dependence and AUD, dark orange) using GWAS methods. Not all references in Table 1 are included in this figure.

Figure 3.

Gene-Phenotype network. Shared and specific genetic contributions at different stages or symptoms associated with alcohol use disorders, including alcohol use, indices of alcohol misuse severity (MaxDrinks, AUDIT-P), alcohol dependence, response to alcohol. Only SNPs in genes showing a significant (P < 10–8) association with multiple AUD and alcoholrelated traits, and available from the GWAS catalog at the time of this writing, are included. AUDIT, Alcohol Use Disorder Identification Test; AUDIT-C, Alcohol Use Disorder Identification Test items 1–3; AD, alcohol dependence; AUD, alcohol use disorder; UKB, UK Biobank; MVP, Million Veterans Program; AlcGen, Alcohol Genome-wide Association Consortium; GSCAN, GWAS & Sequencing Consortium of Alcohol and Nicotine use Consortium; GxE, gene by environment interaction; GWAS, genome-wide association study.

Figure 4.

Heritability and genetic correlation estimates across alcohol use behaviors. Values (%) on the diagonal represent SNP-heritability estimates. Blank boxes represent pairs of traits that are not significantly genetically correlated; - represents a pair of traits that have not been tested.

Figure 5.

GWAS hits discovered as a function of sample size and alcohol use behaviors. AUDIT, Alcohol Use Disorder Identification Test; AUDIT-C, Alcohol Use Disorder Identification Test items 1–3. Interactive plot: http://rpubs.com/sanchezroige/475742