Elsevier

Biological Psychiatry

Volume 87, Issue 7, 1 April 2020, Pages 609-618
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2019.09.011Get rights and content

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.

Section snippets

Design Strategies for Enhancing AUD Genetic Discovery

For decades, candidate gene studies were used to determine the contribution of specific genes that increase risk for AUD. Candidate gene studies tended to focus on genes that influenced pharmacokinetic and pharmacodynamic (e.g., dopaminergic, glutamatergic, and opioid signaling systems) factors. Larger genetic studies have generally not replicated the findings from candidate gene studies (11). An exception is the genes encoding ethanol metabolizing enzymes, particularly alcohol dehydrogenase (

Recent Discoveries on the Molecular Genetics of Alcohol Use Behaviors

Table 1 summarizes the most recent GWASs of alcohol use behaviors (N = 16). Figure 2 provides an overview of the chronology of these studies. Figure 3 shows that the list of genes identified by these studies is highly heterogeneous. These data suggest incomplete genetic overlap between measures of alcohol use behaviors (Figure 4), although ascertainment bias and limited power (see Figure 5) are likely to be additional contributing factors.

The 4q23 region, which contains the genes for several

Polygenic Methods Generate Hypotheses to Test Across Alcohol Use Behaviors

One successful application of GWASs has been their use for assigning polygenic risk scores (PRSs), which provide estimates of an individual’s genetic risk of developing a given disorder. Reassuringly, PRSs for alcohol use behaviors predict equivalent phenotypes in independent cohorts, such as alcohol consumption (51), AD (13), and AUD symptoms (52). E.C. Johnson, Ph.D., et al. (unpublished data, 2019) recently identified that compared with PRSs for alcohol consumption (AUDIT-C), PRSs for

Alcohol Consumption and Misuse Show a Distinct Genetic Architecture

Before the era of large-scale genomic research, twin and family-based studies identified a high degree of genetic overlap between the genetic risk for AUD and psychopathology by modeling correlations among family members, such as Kendler et al. (58). With the recent development of linkage disequilibrium score regression, it is now possible to estimate the genetic correlations between specific alcohol use behaviors (Figures 1 and 4) and a plethora of psychiatric, health, and educational outcomes

Limitations and Future Directions

Before the availability of large population studies and collaborative consortia efforts, few genes were reliably associated with AUD. The use of intermediate traits or endophenotypes (e.g., alcohol consumption as an intermediate phenotype for AUD) has become increasingly common, and multiple new loci have been associated with alcohol use behaviors. Using intermediate phenotypes also facilitates translational research, we can mimic aspects of human alcohol use using animal models, including

Conclusions

AUD is a complex, heterogeneous disorder encompassing a variety of behavioral, psychological, and physiological traits with a complex longitudinal structure, thus posing an enormous challenge for genetic analysis. Instead, AUD can be fractionated into dimensions or symptoms. Several recent GWASs have used this approach, and it is now common to study quantitative measures, including alcohol consumption and aspects of disordered drinking, in large population samples. As a result, GWASs of alcohol

Acknowledgments and Disclosures

This work was supported by the Frontiers of Innovation Scholars Program (Grant No. 3-P3029 [to SS-R]), the Interdisciplinary Research Fellowship in NeuroAIDS (Grant No. MH081482 [to SS-R]), a pilot award from the National Institutes of Health (NIH) (Grant No. DA037844 [to SS-R]) and a 2018 NARSAD Young Investigator Grant (Grant No. 27676 [to SS-R]). This work was also supported by funds from the California Tobacco-Related Disease Research Program (TRDRP) (Grant No. 28IR-0070 and T29KT-0526 [to

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