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Genetic Research Genetic Research Who Is At Risk for Alcoholism? Tatiana Foroud, Ph.D.; Howard J. Edenberg, Ph.D.; and John C. Crabbe, Ph.D. 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 NIAAA­sponsored Collaborative Studies on Genetics of Alcoholism (COGA) has the expressed goal of identifying contributing genes using state­of­the­art genetic technologies. These efforts have ascertained several genes that may contribute to an increased risk of alcoholism, including certain variants encoding alcohol­metabolizing enzymes and neurotransmitter receptors. Genome­wide 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. KEY WORDS: Alcohol dependence; alcoholism; genetics and heredity; genetic theory of alcohol and other drug (AOD) use; genetic causes of AOD use, abuse and dependence (genetic AOD); genetic risk and protective factors; hereditary versus environmental factors; genetic mapping; Collaborative Studies on Genetics of Alcoholism; human studies; animal studies vidence from archeological artifacts The National Institute on Alcohol TATIANA FOROUD, PH.D., is a indicates that fermented beverages Abuse and Alcoholism (NIAAA) Chancellor’s Professor in the Department was founded 40 years ago to further Eexisted as early as 10,000 B.C. of Medical and Molecular Genetics, The excessive consumption of alcohol, understanding of the biological underpinnings of alcohol dependence. Indiana University School of Medicine, however, results in dangers to the Indianapolis, Indiana. health and well being of the drinker Early genetic studies were focused and those around him or her. Today, on delineating whether environmental factors, genetic factors, or both con­ HOWARD J. EDENBERG, PH.D., is a the World Health Organization estimates Distinguished Professor in the Department that alcohol causes 1.8 million deaths tributed to the risk for alcohol depen­ dence. Once it was apparent that of Biochemistry and Molecular Biology (3.2 percent of all deaths) worldwide genetics did indeed play a role in alcohol and the Department of Medical and and 58.3 million (4 percent of total) Molecular Genetics, both at the Indiana 1 dependence, NIAAA began to fund disability­adjusted life­years (DALYs) studies seeking to identify relevant University School of Medicine, lost to disease (http://www.who.int/ Indianapolis, Indiana. substance_ abuse/facts/alcohol/en/ genes. Since then, studies in humans and animals have used complementary index.html). In the United States, alco­ JOHN C. CRABBE, PH.D., is a professor approaches to understand the genetics hol dependence (i.e., alcoholism) is a in the Department of Behavioral of alcohol use and dependence. This major health problem, affecting 4 to 5 Neuroscience, Oregon Health & Science percent of the population at any given overview summarizes the evidence University, and a senior research career time, with a lifetime prevalence of 12.5 1DALYs are a measure of burden of disease. One DALY is equal scientist at the VA Medical Center, percent (Hasin et al. 2007). to 1 healthy year of life lost. Portland, Oregon. 64 Alcohol Research & Health Genetic Research and Risk for Alcoholism supporting a role for genetic factors Strategies for Identifying possible to scan the genome using in alcoholism and describes how new Genes Contributing to a type of genetic variation called genetic findings could affect our Alcohol Dependence microsatellites. In this approach, understanding of the causes and factors called linkage analysis, the pattern contributing to this debilitating disease Researchers have developed several of transmission of a disease (e.g., and could potentially guide the devel­ strategies to identify genes that contribute alcoholism) in families with multiple opment of improved treatments. to differences in the risk for alcohol affected members is compared with dependence, including case–control the pattern of transmission of certain studies and linkage analyses. These microsatellites (see figure 1B). The strategies depend on the premise that Evidence of a Genetic underlying hypothesis is that alcoholics for a particular position in the DNA within a family share many risk alleles; Contribution to Alcohol of these genes, more than one possible Dependence therefore, genes containing alleles form exists. Each of these forms is that increase the risk for alcoholism termed an allele. The study methods Several study designs, including twin, reside within chromosomal regions that used to identify genes that affect the are inherited by most or all alcoholic family, and adoption studies, are used risk for alcohol dependence assume that to determine whether relatively common family members. Unfortunately, how­ the presence of certain alleles increases ever, the chromosomal regions that diseases, such as alcohol dependence, the risk of alcoholism. These variants are caused at least in part by genetic were identified using this approach often that affect risk can be located either factors and to estimate the magnitude contained hundreds or even thousands directly within a gene or near a gene. of genes, making it very challenging of the overall genetic contribution. Case–control studies compare allele to determine which specific gene(s) Twin studies compare the similarity in frequencies in a sample of alcoholic contribute to the risk for alcoholism. disease status (i.e., concordance2) and control subjects. Because DNA between identical (i.e., monozygotic) is inherited from both parents, every The Collaborative Studies on and fraternal (i.e., dizygotic) twins. If person carries two copies of the DNA Genetics of Alcoholism Study risk for a disease (e.g., alcohol depen­ at a given position in the genome— dence) is determined at least in part one allele that was inherited from the Another major advancement in the by genetic factors, monozygotic twins, father and one allele that was inherited search for genes contributing to the who have identical genetic material from the mother. The genotype risk for alcoholism was the initiation (i.e., genomes), would be expected to describes the variation at a particular in 1989 of the NIAAA­funded have a higher concordance rate for position within the genome and is Collaborative Studies on Genetics of alcohol dependence than dizygotic defined by the allele inherited from Alcoholism (COGA), a family study twins, who on average share only half the father and the allele inherited from with the expressed goal of identifying their genome. Studies by several groups the mother. If a given allele contributed contributing genes using newly available have indeed shown higher concordance to the risk for alcohol dependence, genetic technologies (Begleiter et al. 1995; rates for alcohol dependence among one would expect the allele and/or Bierut et al. 2002; Edenberg 2002). The study was groundbreaking in several monozygotic than among dizygotic genotype frequencies to differ between ways, including its size, emphasis on the case and the control subjects (see twins (Agrawal and Lynskey 2008). families, and extensive characterization figure 1A). Family studies, which evaluate the of subjects. In the process, COGA members of a family (both alcoholic Initially, case–control studies often researchers developed a novel assess­ and nonalcoholic members) for the were performed using small numbers of alcoholic and control subjects and ment instrument, the Semi­Structured presence of the disease, also have pro­ examined the role of a single gene, Assessment of the Genetics of Alcoholism vided convincing evidence that the risk frequently testing only for a single (SSAGA), which since has been trans­ for alcohol dependence is determined variation. This approach has limited lated into nine languages and is used partly by genetic influences (Gelernter power, and many results could not be by over 237 investigators worldwide in and Kranzler 2009). Overall, family, studies of alcohol use and dependence. 3 replicated. The most robust result from adoption, and twin studies provide these early studies was the demon­ Families were obtained by recruit­ convergent evidence that hereditary stration that the genes encoding two ing alcohol­dependent probands (i.e., factors play a role in alcohol dependence, alcohol­metabolizing enzymes— index cases) who were in treatment with variations in genes estimated to alcohol dehydrogenase (ADH) and and who gave permission to contact account for 50 to 60 percent of the aldehyde dehydrogenase (ALDH)— total variance in risk. These estimates 2 For a definition of this and other technical terms, see the glossary, played
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