F TWIN, AND adoption studies have convincingly demonstrated that genes play an important role in the development of alcohol dependence, accounting for approximately 50–60% of the population variance (McGue, 1999). Additionally, patterns of alcohol use seem to be under genetic influence. Twin studies have demonstrated that dimensions of alcohol use, such as quantity of alcohol consumed on a typical drinking occasion, frequency of use, and frequency of intoxication, and alcohol metabolism measures, such as time to peak blood alcohol concentration and rate of elimination, are under substantial genetic influence (Heath, 1995). Furthermore, there is evidence of genetic effects on patterns of alcohol use as early as adolescence, and these effects seem to increase over time (Rose et al., 2001). It is unclear to what extent the genes that influence patterns of alcohol use overlap with those that influence alcohol dependence. Despite strong evidence for genetic effects contributing to alcoholism susceptibility, detecting the specific genes that increase or decrease the risk for alcoholism has proven difficult. Many factors contribute to the slow progress in isolating the genes involved in drinking behavior. Many genes are thought to contribute to alcoholism susceptibility, and different genes are likely contributing to alcohol dependence in different individuals. Additionally, the environment plays a substantial role in drinking patterns, with nearly half of the variance in drinking patterns and alcohol dependence attributed to environmental factors. Furthermore, these genes and environments probably interact. Data from a Finnish twin study of alcohol use among adolescents demonstrated that the magnitude of genetic influences can vary dramatically between environments, with up to 5-fold differences demonstrated in different environments (Dick et al., 2001). This suggests that some environments may exacerbate the expression of genetic predispositions, whereas others may be protective. Finally, there is substantial phenotypic heterogeneity in the manifestation of alcohol dependence, with alcoholics differing on dimensions such as age of onset of problems, alcohol symptoms, drinking history, and comorbid disorders. Some evidence suggests that genes may be more important in certain subtypes of alcoholics (Cloninger et al., 1981). Other investigators have studied endophenotypes as a means to deal with the substantial heterogeneity involved in alcohol dependence. Endophenotypes are phenotypes that are thought to be intermediaries between a particular disorder and the biological processes that lead to the manifestation of this disorder. For example, brain wave activity, as measured by electroencephalogram (EEG) and eventrelated potential (ERP), has been studied as an endophenotype for both alcohol dependence and schizophrenia. It is possible that genes act more directly on an endophenotype, as compared with a diagnostic classification, and, therefore, the study of endophenotypes may more efficiently lead to the identification of genes. All of these factors considerably complicate efforts to identify the genes involved in alcohol dependence and to understand the contribution of any specific gene that is identified. A number of genetic strategies have been used in the study of alcohol dependence. These include both linkage and association studies. Linkage studies involve the ascertainment of families with multiple affected individuals; genotyping of segments of DNA that exhibit variation, called polymorphic markers, is often used to detect chromosomal regions in which affected individuals within a family demonstrate increased sharing of a particular marker allele, suggesting that there may be a gene nearby involved in the disorder. Association studies can use either families or unrelated controls; they test the association between a particular allele at a candidate gene and a specific outcome across families. Association methods typically can detect significant effects over much smaller physical distances as compared with linkage studies. For a more extensive review of the methods used in genetic studies, see Dick and Foroud (2003). Here we review the evidence for candidate genes that have been implicated in genetic studies of alcohol dependence and related phenotypes, such as quantitative indices of alcohol use, and endophenotypes, such as EEG. This review is not meant to be exhaustive in reporting all candidate genes, but, rather, covers in detail many of the candidate genes currently thought to be most promising. From the Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana. Received for publication September 30, 2002; accepted February 12, 2003. Supported by NIH Grants AA13358, AA00285, and AA07611. Reprint requests: Tatiana Foroud, PhD, Department of Medical and Molecular Genetics, Indiana University School of Medicine, 975 W. Walnut St., IB-130, Indianapolis, IN 46202-525; Fax: 317-274-2387; E-mail: tforoud@iupui.edu. Copyright © 2003 by the Research Society on Alcoholism.

Candidate Genes for Alcohol Dependence: A Review of Genetic Evidence From Human Studies

Background : Recent advances in the field of acetaldehyde (AcH) research have raised the need for a comprehensive review on the role of AcH in the actions of alcohol. This update is an attempt to summarize the available AcH research.



Methods : The descriptive part of this article covers not only recent research but also the development of the field. Special emphasis is placed on mechanistic analyses, new hypotheses, and conclusions.



Results : Elevated AcH during alcohol intoxication causes alcohol sensitivity, which involves vasodilation associated with increased skin temperature, subjective feelings of hotness and facial flushing, increased heart and respiration rate, lowered blood pressure, sensation of dry mouth or throat associated with bronchoconstriction and allergy reactions, nausea and headache, and also reinforcing reactions like euphoria. These effects seem to involve catecholamine, opiate peptide, prostaglandin, histamine, and/or kinin mechanisms. The contribution of AcH to the pathological consequences of chronic alcohol intake is well established for different forms of cancer in the digestive tract and the upper airways. AcH seems to play a role in the etiology of liver cirrhosis. AcH may have a role in other pathological developments, which include brain damage, cardiomyopathy, pancreatitis, and fetal alcohol syndrome. AcH creates both unpleasant aversive reactions that protect against excessive alcohol drinking and euphoric sensations that may reinforce alcohol drinking. The protective effect of AcH may be used in future treatments that involve gene therapy with or without liver transplantation.



Conclusions : AcH plays a role in most of the actions of alcohol. The individual variability in these AcH-mediated actions will depend on the genetic polymorphism, not only for the alcohol and AcH-metabolizing enzymes but also for the target sites for AcH actions. The subtle balance between aversive and reinforcing, protecting and promoting factors will determine the overall behavioral and pathological developments.

The Role of Acetaldehyde in the Actions of Alcohol (Update 2000)

Genetic polymorphism of alcohol dehydrogenase in europeans: the ADH2*2 allele decreases the risk for alcoholism and is associated with ADH3*1.

The alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs) that metabolize ethanol are polymorphic. Different alleles encode subunits of the enzymes that differ in their rate of metabolizing ethanol. These polymorphisms are distributed differently among populations and have been shown to influence the risk for alcoholism in some Asian populations. We have examined the allele frequencies at the ADH2, ADH3, and ALDH2 loci in four populations from China (Han, Mongolian, Korean, and Elunchun) and in alcoholics within each population. The four populations differ in allele frequencies, with the Elunchun having a much lower frequency of ADH2*2 alleles, and the Mongolian and Elunchun having a much lower frequency of ALDH2*2 alleles. Within each population, alleles at one or more of these three loci are protective against alcoholism, although the populations differ in which loci play significant roles. The protective allele at each locus (ALDH2*2, ADH2*2, and ADH3*1) encodes a subunit that either metabolizes ethanol to acetaldehyde more rapidly or slows the conversion of acetaldehyde to acetate. Taken as a whole, data demonstrate that genetic differences in the enzymes that metabolize alcohol can substantially affect the risk for alcoholism.

Polymorphism of ADH and ALDH genes among four ethnic groups in China and effects upon the risk for alcoholism.

The Collaborative Study on the Genetics of Alcoholism (COGA) is a multicenter research program to detect and map susceptibility genes for alcohol dependence and related phenotypes. The measure M of "maximum number of drinks consumed in a 24-hour period" is closely related to alcoholism diagnosis in this dataset and provides a quantitative measure to grade nonalcoholic individuals. Twin studies have shown log(M) to have a heritability of approximately 50%. Genome screens for this trait were performed in two distinct genotyped samples (wave 1 and wave 2), and in the combined sample. MAPMAKER/SIBS was used to carry out Haseman-Elston based regression analyses. On chromosome 4, an unweighted all-pairs multipoint LOD of 2.2 was obtained between D4S2407 and D4S1628 in wave 1; in wave 2, the region flanked by D4S2404 and D4S2407 gave a LOD of 1.5. In the combined sample, the maximal LOD was 3.5 very close to D4S2407. This evidence for linkage is in the region of the alcohol dehydrogenase gene cluster on chromosome 4. These findings on chromosome 4 are consistent with a prior report from COGA in which strictly defined nonalcoholic subjects in wave 1 were analyzed. The present analysis on log(M) allows more individuals to be included and thus is potentially more powerful.

A genome screen of maximum number of drinks as an alcoholism phenotype.

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), the principal enzymes responsible for oxidative metabolism of ethanol, exist in multiple, genetically determined molecular forms. Widely different kinetic properties in some of these isozymes account for the individual differences in alcohol sensitivity. In this study we used the polymerase chain reaction/restriction fragment length polymorphism method to determine the genotypes of the ADH2 and ALDH2 loci of alcoholic and nonalcoholic Chinese living in Shanghai. We also investigated the subjects' drinking patterns by means of semistructured interviews. The alcoholics had significantly lower frequencies of the ADH22 and ALDH22 alleles than did the nonalcoholics, suggesting the inhibitory effects of these alleles for the development of alcoholism. In the nonalcoholic subjects, ADH22 had little, if any, effect, despite the significant effect of the ALDH22 allele in decreasing the alcohol consumption of the individual. Taken together, these results fit the proposed hypothesis for the development of alcoholism, i.e., drinking behavior is greatly influenced by the individual's gentoypes of alcohol-metabolizing enzymes, and the risk of becoming alcoholic is proportionate with the ethanol consumption of the individual.

https://link.springer.com/content/pdf/10.1007/BF00207371.pdf

Hu Kou-Bao

Papers

Alcohol and aldehyde dehydrogenase genotypes and drinking behavior of Chinese living in Shanghai