Evidence-Based Reviews

Can genetics predict risk for alcohol dependence?

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

Victor M. Karpyak, MD, PhD

Daniel K. Hall-Flavin, MD

David A. Mrazek, MD, FRCP

Inherited variations affect response to alcohol and to alcoholism treatments.

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References

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Children of alcoholics have a 40% to 60% increased risk of developing severe alcohol-related problems¹—a harsh legacy recognized for >30 years. Now, as the result of rapidly growing evidence, we can explain in greater detail why alcoholism runs in families when discussing alcohol dependence with patients.

Individuals vary in response to medications and substances of abuse, and genetic research is revealing the heritable origins. Numerous genetic variations are known to influence response to alcohol, as well as alcoholism’s pathophysiology, clinical manifestations, and treatment. Pieces are still missing from this complex picture, but investigators are identifying possible risk factors for alcoholism and matching potential responders with treatments such as naltrexone and acamprosate.

This article provides a progress report on contemporary genetic research of alcoholism. Our goal is to inform your clinical practice by describing:

new understandings of the genetics of alcoholism
how researchers identify relationships between genetic variations and clinical/behavioral phenomena
practical implications of this knowledge.

Genetic variations and risk of addiction

No single gene appears to cause alcoholism. Many genetic variations that accumulated during evolution likely contribute to individual differences in response to alcohol and susceptibility to developing alcohol-related problems. A growing number of genetic variations have been associated with increased alcohol tolerance, consumption, and other related phenotypes.

Like other addictive substances, alcohol triggers pharmacodynamic effects by interacting with a variety of molecular targets (Figure 1).² These target proteins in turn interact with specific signaling proteins and trigger responses in complex functional pathways. Genetic variations may affect the structure of genes coding for proteins that constitute pathways involved in alcohol’s effects on target proteins (pharmacodynamics) or its metabolism (pharmacokinetics). If such variations alter the production, function, or stability of these proteins, the pathway’s function also may be altered and produce behavioral phenotypes—such as high or low sensitivity to alcohol’s effects.

Alcoholism-related phenotypes. DSM-IV-TR diagnostic criteria include some but not all of the multiple phenotypes within alcoholism’s clinical presentation. Researchers in the Collaborative Studies on Genetics of Alcoholism (COGA)³ identified chromosome regions linked to alcoholism-related phenotypes, including:

alcohol dependence⁴
later age of drinking onset and increased harm avoidance⁵
alcoholism and depression⁶
alcohol sensitivity⁷
alcohol consumption.⁸

To identify genes of interest within these chromosome regions, researchers used transitional phenotypes (endophenotypes) that “lie on the pathway between genes and disease,”^9,10 and allowed them to characterize the neural systems affected by gene risk variants.¹¹ As a result, they found associations among variations in the GABRA2 gene, (encoding the alpha-2 subunit of the GABAA receptor), specific brain oscillations (electrophysiologic endophenotype), and predisposition to alcohol dependence.^12,13 By this same strategy, researchers discovered an association between the endophenotype (low-level of response to alcohol) and some genotypes, including at least 1 short allele of the serotonin transporter gene SLC6A4.¹⁴

Figure 1
Known molecular targets for alcohol and other drugs of abuse

Effects of drugs of abuse (black arrows) influence intracellular signaling pathways (blue arrows) to produce immediate and long-term changes in cell function.
cAMP: cyclic adenosine monophosphate; GABAA: gamma-aminobutyric acid A receptor; Gi, Gs, Gq: G proteins (heterotrimeric guanine nucleotide-binding proteins) MAPK: mitogen-activated protein kinase; N-cholino receptor: nicotinic cholinoreceptor; NMDA: N-methyl-D-aspartate; PKA: protein kinase A
Source: Created for CURRENT PSYCHIATRY from information in reference 2

Alcohol metabolism

Alcohol is metabolized to acetic acid through primary and auxiliary pathways involving alcohol and acetaldehyde dehydrogenases (ADH/ALDH) and the microsomal ethanol oxidizing system (cytochrome P-450 [CYP] 2E1)¹⁵ (Figure 2). Auxiliary pathways become involved when the primary pathway is overwhelmed by the amount of alcohol needed to be metabolized. Catalase and fatty acid ethyl ester synthases play a minor role under normal conditions but may be implicated in alcohol-induced organ damage.¹⁶

Clinical Point

From one individual to another, the ability to metabolize ethyl alcohol varies up to 3- to 4-fold

ADH/ALDH pathway. From one individual to another, the ability to metabolize ethyl alcohol varies up to 3- to 4-fold.¹⁷ In European and Amerindian samples, a genetic link has been identified between alcoholism and the 4q21-23 region on chromosome 4.¹⁸ This region contains a cluster of 7 genes encoding for alcohol dehydrogenases (ADH), including 3 Class I genes—ADH1A, ADH1B, and ADH1C—coding for the corresponding proteins that play a major role in alcohol metabolism.¹⁹ In eastern Asian samples, alleles encoding high activity enzymes (ADH1B*47His and ADH1C*349Ile) are significantly less frequent in alcoholics compared with nonalcoholic controls.²⁰

Mitochondrial ALDH2 protein plays the central role in acetaldehyde metabolism and is highly expressed in the liver, stomach, and other tissues—including the brain.²¹ The ALDH2*2 gene variant encodes for a catalytically inactive enzyme, thus inhibiting acetaldehyde metabolism and causing a facial flushing reaction.²² The ALDH2*2 allele has a relatively high frequency in Asians but also is found in other populations.²³ Meta-analyses of published data indicate that possessing either of the variant alleles in the ADH1B and ALDH2 genes is protective against alcohol dependence in Asians.²⁴