Evidence-Based Reviews

Can genetics predict risk for alcohol dependence?

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

References

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Challenges are associated with GWAS, however, and include:

need for substantial numbers (2,000 to 5,000) of rigorously described cases and matched controls
need for accurate, high-throughput genotyping technologies and sophisticated algorithms for analyzing data
risk of high false-positive rates related to multiple testing
inability to scan 100% of the genome, which may lead to false-negative findings.

Table

Examples of gene variations related to alcohol misuse and alcoholism phenotypes

Phenotype	Gene variation(s)
Related to alcohol misuse
Low response/high tolerance to alcohol	L allele of serotonin transporter gene (SLC6A4) and Ser385 allele of alpha-6 subunit of GABAA receptor gene (GABRA6) in adolescents and healthy adult men;^a,b 600G allele of alpha-2 subunit of GABAA receptor gene (GABRA2) in healthy social drinkers^c
Cue-related craving for alcohol	118G allele of opioid μ-receptor gene (OMPR) and L allele of dopamine receptor type 4 gene (DRD4) in young problem drinkers^d,e
Binge drinking	S allele of serotonin transporter gene in college students; combination of SS genotype of serotonin transporter gene and HH genotype of MAOA gene in young women^f
Related to alcoholism
Alcohol dependence	Two common haplotypes of GABRA2 gene^g
Liver cirrhosis in alcoholics	-238A allele of tumor necrosis factor gene (TNFA)^h
Protects against withdrawal symptoms in alcoholics	-141C Del variant of the dopamine receptor type 2 gene (DRD2)ⁱ
Associated with delirium tremens	8 genetic polymorphisms in 3 candidate genes involved in the dopamine transmission (DRD2, DRD3, and SLC6A3), 1 gene involved in the glutamate pathway (GRIK3), 1 neuropeptide gene (BDNF), and 1 cannabinoid gene (CNR1)^j
Associated with alcohol withdrawal seizures	9 repeat allele of dopamine transporter (SLC6A3); 10 repeat allele of tyrosine hydroxylase gene (TH); Ser9 allele of dopamine receptor type 3 gene (DRD3); SS genotype of serotonin transporter gene; 2108A allele in NR1 subunit of NMDA receptor gene (GRIN1)^k-m
GABAA: gamma-aminobutyric acid A; MAOA: monoamine oxidase A; NMDA: N-methyl-D-aspartate
Source: Click here to view references

Figure 3
2 ways to seek relationships between genes and behavior

Researchers use ‘forward’ and ‘reverse’ genetics to connect behavioral phenotypes with predisposing genotypes. Each approach must consider intermediary functional anatomic and physiologic levels (black box), as shown in this conceptual framework.
DA: dopamine; EEG: electroencephalography; 5-HT: serotonin; LTD: long-term depression; LTP: long-term potentiation; RNA: ribonucleic acid; SNPs: single nucleotide polymorphisms; VNTRs: variable number tandem (triplet) repeats

Clinical implications

Genomic research is increasing our understanding of alcohol’s pharmacokinetic and pharmacodynamic interactions and of potential genetic associations with alcoholic phenotypes. These insights may lead to discovery of new therapies to compensate for specific physiologic and behavioral dysfunctions. For example, medications with pharmacologic profiles complimentary to addiction-related physiologic/behavioral deficits might be designed in the future.

Clinical Point

Associations found between genomic variations and phenotypes related to alcoholism must be replicated to rule out false positives

Likewise, new understandings about genetic variability may allow us to predict an individual’s ability to tolerate and respond to existing medications used to treat alcohol dependence. For example, in studies of alcoholic and nonalcoholic subjects:

Individuals with the 118G variant allele of the μ-opioid receptor may experience a stronger subjective response to alcohol and respond more robustly to naltrexone treatment than do carriers of the more common 118A allele.³²
Persons with a functional variation in the DRD4 gene (7 repeat allele–DRD4L) coding for type 4 dopamine receptor reported greater euphoria and reward while drinking alcohol and reduced alcohol consumption during 12-week treatment with olanzapine, a DRD2/DRD4 blocker.³³

Applying this approach to the study of acamprosate has been difficult because of uncertainty about which protein molecules it targets. Variation in the Per2 gene (coding for protein involved in the circadian cycle) has been shown to be associated with brain glutamate levels, alcohol consumption, and the effects of acamprosate, although these interactions require further investigation.³⁴

Clinical Point

Individuals with a variant allele of the μ-opioid receptor may respond better to naltrexone than do carriers of the more common allele

Pharmacogenomics of alcoholism treatment is in a very early stage of development. Findings require replication in different clinical samples and functional analysis. At the same time, if the reported association between the μ-opioid receptor genetic variation and naltrexone’s treatment efficacy is confirmed, this finding could help to guide clinical practice. Studies of genomic predictors of other medications’ efficacy and tolerability for alcoholism treatment would be expected to follow.

Related resources

National Institute on Alcohol Abuse and Alcoholism. Collaborative Studies on Genetics of Alcoholism (COGA). www.niaaa.nih.gov (search NIAAA-funded collaborative research programs).
Dick DM, Jones K, Saccone N, et al. Endophenotypes successfully lead to gene identification: results from the Collaborative Study on the Genetics of Alcoholism. Behav Genet 2006;36(1):112-26.

Drug brand names

Acamprosate • Campral
Naltrexone • ReVia, Vivitrol
Olanzapine • Zyprexa

Disclosure