Evidence-Based Reviews

Can genetics predict risk for alcohol dependence?

Current Psychiatry. 2008 March;7(3):57-73

References

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The ADH4 enzyme catalyzes oxidation or reduction of numerous substrates—including long-chain aliphatic alcohols and aromatic aldehydes—and becomes involved in alcohol metabolism at moderate to high concentrations. The -75A allele of the ADH4 gene has promoter activity more than twice that of the -75C allele and significantly affects its expression.²⁵ This substitution in the promoter region, as well as A/G SNP (rs1042364)—a single nucleotide polymorphism (SNP)—at exon 9, has been associated with an increased risk for alcohol and drug dependence in European Americans.²⁶

Finally, variations in the ADH7 gene may play a protective role against alcoholism through epistatic effects.²⁷

The CYP 2E1 pathway has low initial catalytic efficiency compared with the ADH/ALDH pathway, but it may metabolize alcohol up to 10 times faster after chronic alcohol consumption or cigarette smoking and accounts for metabolic tolerance.²⁸ CYP 2E1 is involved in metabolizing both alcohol and acetaldehyde.²⁹ The CYP 2E1*1D polymorphism has been associated with greater inducibility as well as alcohol and nicotine dependence.³⁰

Thus, linkage and association studies support the association of phenotypes related to alcohol response and dependence with variations in genes that code for proteins involved in alcohol’s pharmacodynamic and pharmacokinetic effects. Each of these findings is important, but conceptual models organizing them all and explaining their role in alcohol’s effects and predisposition to alcoholism have yet to be constructed.

Figure 2
Genetic variations that affect alcohol metabolism pathways

Genetic variations affect the efficiency of primary and auxiliary pathways by which ethyl alcohol is metabolized to acetaldehyde and acetic acid. Auxiliary pathways become involved when the primary pathway is overwhelmed by the amount of alcohol to be metabolized.
ADH: alcohol dehydrogenase; ALDH: acetaldehyde dehydrogenase; P450CYP 2E1: cytochrome P450, family 2, subfamily E, polypeptide 1; A/G SNP: adenine/guanine single nucleotide polymorphism

Phenotype-genotype relationships

Alcohol—unlike most other addictive substances—does not have a specific receptor and is believed to act by disturbing the balance between excitatory and inhibitory neurotransmission in the neural system. Consequently, researchers explore relationships between genetics and alcohol-related problems using 2 approaches:

Forward genetics (discovering disease-related genes via genome-wide studies and then studying their function; examples include linkage and genome-wide association studies [GWAS]).
Reverse genetics (testing whether candidate genes and polymorphisms identified in animal studies as relevant for biological effects also exist in humans and are relevant to the phenotype).³¹

Clinical Point

CYP 2E1 may metabolize alcohol up to 10 times faster after chronic alcohol consumption or cigarette smoking

When searching for relationships between genotypes and phenotypes, both approaches must take into account a framework of functional anatomic and physiologic connections (Figure 3).

Linkage studies. The goal of linkage studies is to find a link between a phenotypic variation (ideally a measurable trait, such as number of drinks necessary for intoxication) and the chromosomal marker expected to be in the vicinity of the disease-specific gene variation. An advantage of linkage studies is that they can be started without knowing specific DNA sequences. Their limitations include:

limited power when applied to complex diseases such as alcoholism
they do not yield gene-specific information
their success is highly dependent on family members’ willingness to participate.

Association studies. Candidate gene-based association studies are designed to directly test a potential association between the phenotype of interest and a known genomic sequence variation. This approach provides adequate power to study variations with modest effects and allows use of DNA from unrelated individuals. The candidate gene approach has revealed associations between specific genomic variations and phenotypes related to alcohol misuse and alcoholism (Table).

Like linkage studies, association studies have their own challenges and limitations, such as:

historically high false-positive rates
confounding risks (allele frequencies may vary because of ethnic stratification rather than disease predisposition).

Clinical Point

Alcohol is believed to act by disturbing the balance between excitatory and inhibitory neurotransmission in the neural system

To address these challenges, researchers must carefully choose behavioral, physiologic, or intermediate phenotypes and genotype variations, as well as control subjects and sample sizes. Replication studies are necessary to rule out false-positive associations. In fact, only some of the findings depicted in the Table—those related to GABRA2 and GABRA6 and few other genes—have been replicated.

Genome-wide association studies are a powerful new method for studying relationships between genomic variability and behavior. With GWAS, thousands of DNA samples can be scanned for thousands of SNPs throughout the human genome, with the goal of identifying variations that modestly increase the risk of developing common diseases.

Unlike the candidate gene approach—which focuses on preselected genomic variations—GWAS scans the whole genome and may identify unexpected susceptibility factors. Unlike the family-based linkage approach, GWAS is not limited to specific families and can address all recombination events in a population.