Genetic research: who is at risk for alcoholism.
- Authors
- Foroud, Tatiana; Edenberg, Howard J; Crabbe, John C
- Year
- 2010
- Journal
- Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism
- PMID
- 23579937
- PMCID
- PMC3887503
The National Institute on Alcohol Abuse and Alcoholism (NIAAA) was founded 40 years ago to help elucidate the biological underpinnings of alcohol dependence, including the potential contribution of genetic factors. Twin, adoption, and family studies conclusively demonstrated that genetic factors account for 50 to 60 percent of the variance in risk for developing alcoholism. Case-control studies and linkage analyses have helped identify DNA variants that contribute to increased risk, and the NIAAA-sponsored Collaborative Studies on Genetics of Alcoholism (COGA) has the expressed goal of identifying contributing genes using state-of-the-art genetic technologies. These efforts have ascertained several genes that may contribute to an increased risk of alcoholism, including certain variants encoding alcohol-metabolizing enzymes and neurotransmitter receptors. Genome-wide association studies allowing the analysis of millions of genetic markers located throughout the genome will enable discovery of further candidate genes. In addition to these human studies, genetic animal models of alcohol's effects and alcohol use have greatly advanced our understanding of the genetic basis of alcoholism, resulting in the identification of quantitative trait loci and allowing for targeted manipulation of candidate genes. Novel research approaches-for example, into epigenetic mechanisms of gene regulation-also are under way and undoubtedly will further clarify the genetic basis of alcoholism.
Approaches to identifying genes contributing to the risk of alcoholism. A) Case–control association study design. Each circle represents a person who is either an alcoholic (case subject) or not an alcoholic (control subject). The study assesses the role of a single-nucleotide polymorphism (SNP)* that exists in two different variants (i.e., alleles)—allele 1 and allele 2. Because each person inherits two copies of the SNP from their parents, the numbers in the circles represent the three possible genotypes (11, 12, and 22). Many more case than control subjects carry at least one copy of allele 1 (i.e., have the 11 and 12 genotypes), suggesting that people with allele 1 may be more likely to develop alcoholism. B) Linkage study design. A three-generation family tree (pedigree) is shown. Squares represent male subjects and circles represent female subjects. Shaded symbols represent alcoholic individuals and unshaded symbols represent nonalcoholic individuals. In this pedigree, there are alcoholic individuals in each generation, and both men and women are affected.NOTE: *An SNP is a DNA sequence variation occurring when a single nucleotide in a DNA marker (or other genetic sequence) differs between members of a species or between the chromosome pairs in an individual.
The main steps of alcohol metabolism. Alcohol first is metabolized to acetaldehyde by the enzyme alcohol dehydrogenase (ADH), which is encoded by several genes, each of which may exist in several variants (i.e., alleles). Certain alleles encode ADH molecules that result in the metabolism of alcohol (denoted by the red arrow above ADH). As a result, buildup of acetaldehyde occurs (denoted by the upward-pointing arrow), leading to such aversive effects as nausea, flushing, and accelerated heart beat (i.e., tachycardia). The acetaldehyde then is metabolized to acetate by the enzyme aldehyde dehydrogenase (ALDH), which also is encoded by several genes existing in different alleles. Certain alleles in the ALDH2 gene, which encodes a key ALDH enzyme, can result in very low activity of the enzyme (denoted by the black arrow with a red line through it), again causing acetaldehyde accumulation and the resulting aversive effects.
| # | Section | Preview |
|---|---|---|
| 40 | Studies of Gene–Environment Interaction | A recent review has discussed several important features of gene–environment interaction research… |
| 41 | Studies of Gene–Environment Interaction | Analysis of human gene–environment interactions also are complicated by the fact that these… |
| 42 | Future Directions | Research into the genetics of alcoholism, both in humans and in animal models, has made great… |
| 43 | Future Directions | MicroRNAs—short RNA molecules naturally encoded by the genome that can bind to certain mRNA… |
| 44 | Future Directions | In summary, the genetics field has undergone a technological revolution, particularly in the past… |
| 45 | Future Directions | Another challenge is to relate the complex human behavioral phenotypes to specific variations in the… |
| 46 | Future Directions | The identification of any genes that appear important in alcoholism susceptibility provides an… |
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| Validating Harmful Alcohol Use as a Phenotype for Genetic Discovery Using Phosphatidylethanol and a Polymorphism in ADH1B. | 2017 | 28295416 |
| Genetics and alcoholism. | 2013 | 23712313 |
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| The genetics of alcohol dependence. | Rietschel M et al. | — | 2013 | → |
| Bridging Animal and Human Models: Translating From (and to) Animal Genetics. | Barkley-Levenson AM et al. | — | 2012 | → |
| Translational behaviour-genetic studies of alcohol: are we there yet? | Crabbe JC | — | 2012 | → |