- Email: [email protected]
Alcoholism
Alcoholism TJ Phillips, Oregon Health & Science University, Portland, OR, USA; Veterans Affairs Medical Center, Portland, OR, USA
© 2013 Elsevier Inc. All rights reserved.
This article is a revision of the previous edition article by KE Browman, JC Crabbe, volume 1, pp 27–29, © 2001, Elsevier Inc.
Glossary Alcohol tolerance A diminished response to alcohol that may occur after previous exposure to alcohol. A larger dose of alcohol may be needed to produce the level of response seen after the initial exposure. Alcohol withdrawal Behavioral or physiological symptoms that may occur when exposure to alcohol is removed. Symptoms may include reduced activity levels, headache, and mild or severe seizures. Symptoms may be seen after an acute high dose of alcohol and increase in severity with more chronic alcohol exposure. Allele An alternative form of a gene. These are identified as different DNA sequences. Candidate gene A gene thought to influence a trait or disease. Case-control (candidate gene) study Comparisons of individuals with a particular disease (case) to those without the disease (control) for the frequency of a particular candidate gene allele. In a well-designed study, the cases and controls are matched on characteristics such
Clinical Findings Dependence on alcohol may include tolerance, withdrawal symptoms, and other severe medical consequences. Why do some individuals who engage in binge-like drinking at one stage of their lives manage ultimately to consume alcoholic beverages in moderation, while others develop significant and debilitating use disorders? The answer to this question is critical to prevention and treatment. Studies making use of compar isons between individuals who share many or few similar genes established the familial nature of alcoholism decades ago. Since that time, studies have been conducted in which a parti cular gene has been the focus and the frequency of that gene in alcohol-dependent individuals has been compared to its fre quency in nondependent individuals. Using this case-control method, evidence for the involvement of some genes in alcohol dependence, such as a dopamine receptor gene (DRD2), the dopamine transporter gene (SLC6A3/DAT1), the mu-opioid receptor gene (OPRM1), and a gamma-aminobutyric acid (GABA) receptor gene (GABARA2), among others, has been obtained, although results have sometimes appeared spurious or specific to particular populations. The most consistent find ing has been for the involvement of genes involved in alcohol metabolism, the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes. Certain variants of these genes have been known for many years to protect individuals from developing alcoholism, due largely to the aversive effects of increased levels in these individuals of one by-product of alco hol use, acetaldehyde.
62
as age, sex, socioeconomic status, educational level, and others. Genome-wide association study (GWAS) An examination of associations between genetic variants (alleles) across the entire genome and a disease trait. Knockout mouse A mouse in which a gene has been altered (knocked out) by genetic engineering, so that the gene no longer operates properly. Microarray Sometimes called a gene chip. A solid support (a membrane, glass or plastic slide) on which DNA sequences have been affixed and will interact (or hybridize) with specific sequences that may be found in brain or other biological samples. Fluorescent dyes are used to measure these interactions and provide a measure of gene expression. Quantitative trait locus (QTL) A gene at a particular location in the genome that influences the level of a quantitative trait. A quantitative trait is influenced by more than one gene; thus, a single QTL accounts for only some portion of the variation in that trait.
In addition to using alcohol dependence or alcoholism diag nosis as the trait in genetic analyses, human genetic studies have been conducted using frequency or amount of alcohol use and sensitivity to particular effects of alcohol, to categorize indivi duals and apply newer methods of genetic analysis. One such method is genome-wide association (GWAS). This method examines all or most of the genes that appear in different forms (genetic variants or alleles) in different individuals, in an attempt to identify those that are associated with alcoholism or with alcoholism-related traits. Individuals are often separated into cases and controls in this analysis. However, one important difference between this method and the case-control method described above is that this method does not limit the analysis to a specific candidate gene. Thus, GWAS has the potential for identifying novel genes and mechanisms that influence addic tion. The promising associations that have been found to date for various alcoholism-relevant phenotypes will require addi tional examination before definitive conclusions can be reached. Another sophisticated method is whole genome expression profiling. Rather than looking for differences in the form of a gene, this method examines differences in the amount of the gene’s coded information that is produced or expressed. This is done by using a microarray to determine gene expression level. A microarray is most commonly a glass or plastic slide on which different gene sequences have been placed that can interact with genetic material extracted from the brain or other biological samples. Gene expression has been compared between alcohol-dependent individuals and nondependent controls. Among the differences that have been found are differences in
Brenner’s Encyclopedia of Genetics, 2nd Edition, Volume 1
doi:10.1016/B978-0-12-374984-0.00028-0
Alcoholism the expression of genes important for glutamate functioning, a molecule that controls excitation in the brain. Differences have also been found in the expression of oligodendroglia-related genes that are important for the physical support of cells and for their appropriate functioning. Because brain samples are needed to perform expression profiling for central nervous system dis eases, these studies can only be performed using postmortem tissue. Therefore, one important question that remains unan swered is whether the differences existed before alcohol dependence developed or whether they are the result of excessive alcohol use. Both questions are important. Currently, many minds are working on the problem of cohesively analyzing the massive data sets from these different technologies to identify the brain gene networks that are important in alcoholism.
Findings from Animal Models Rodents have been particularly useful for studying traits that are thought to be relevant to human alcoholism. However, research in fruit flies (Drosophila melanogaster) and worms (Caenorhabditis elegans) have produced genetic results for alcohol effects, some of which are remarkably similar to those found in rodents and humans. Genetic similarity between mice and humans is about 80%. Therefore, genes of importance found in mouse studies can be identified and followed up in human studies, and vice versa. A particular advantage of collecting data in rodent models of human alcohol-related effects and problems is the ability to control alcohol exposure, environmental conditions during rear ing and in adulthood, and even genetic constitution. For example, the effects of several genes have been studied in mice by mutating the gene so that it no longer functions and then studying whether mice that have the mutant gene show a change in alcohol drinking or sensitivity. The mouse form of DRD2 (Drd2) has been studied in this way. Mice with the Drd2 gene have been compared to mutant mice (also called ‘knockout mice’) and have been found to drink less alcohol and show less preference for a place where they were previously given alcohol. These results, along with findings in human alcoholics, lend credence to a role for DRD2 in alcoholism. One method that can be used in animals, but not humans, is selective breeding. Individuals are chosen, for example, that show high levels of alcohol drinking and they are bred to each other to see if their offspring will also have a high level of drinking. Their level of drinking is compared to the offspring of mice that were produced by individual mice that did not drink much alcohol. In fact, these studies have shown that amount of alcohol consumed can be bred for, as can level of behavioral stimulation and level of behavioral sedation produced by alcohol. Several rat and mouse selected lines have been produced in this way and studied for genetic, biochemical, and other behavioral differences. For exam ple, neuropeptide Y (NPY), a natural substance that is produced in the brain and has long been known to stimulate eating, has been studied in lines of rats bred for high and low levels of alcohol drinking. Some drugs that block the NPY signal by keep ing it from binding to its receptor reduced alcohol drinking in an alcohol-preferring rat line. Recently, a study in nonhuman pri mates has supported a role for genetic variation in the NPY gene in susceptibility to heightened alcohol use following stress, and
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there are promising data in human studies as well. Based on the convergent data, some clinical researchers are advocating combi nation therapies for alcoholism that include manipulation of NPY. Finally, a method called quantitative trait locus (QTL) map ping has been used to identify the chromosomal locations of genes that influence traits that are relevant to alcoholism. The alcohol responses of animals that are genetically different either throughout many parts of their genome, or just in one small region, are measured. Then, their response differences are compared to their genetic differences. The QTL analysis will detect whether a particular gene sequence or allele is present in individuals with high scores but mostly absent in individuals with low scores. This procedure was also used to study the severity of the behavioral reactions seen in mice when alcohol was taken away, or withdrawn, after they had been exposed to a high dose of alcohol. Whether the mice carried one allele or another for the gene, Mpdz, was found to be important for how severe the withdrawal reactions were. In several studies, it has been found that mice that have more severe alcohol withdrawal reactions are less likely to drink a lot of alcohol. Therefore, this gene may serve a protective role against high alcohol drinking and is being studied in humans.
Conclusions The last decade has seen advancements in technologies that have made it possible to go beyond the simple demonstration that alcoholism has a genetic component. Evidence from ani mal and human studies is converging on specific genes with roles in alcohol use disorders and their associations with spe cific biochemical pathways. Described herein is how genome-wide measures of genetic variants and of gene expres sion are being used to identify such genes. The identification of influential biochemical pathways is an important goal for the development of more effective medications for alcoholism.
Acknowledgements Supported by the Department of Veterans Affairs and NIH NIAAA grants P60AA010760 and U01AA016655.
See also: Additive Genetic Variance; Allele Frequency; Behavioral Genetics; Bioinformatics; Breeding of Animals; Candidate Gene; Centimorgan (cM); Chromosome Mapping; Complex Locus; Complex Traits; Continuous Variation; Deletion Mapping; Deletion Mapping, Mouse; Deletion Mutation; DNA Marker; DNA Sequencing; Gene; Gene Expression; Gene Frequency; Gene Mapping; Genetic Diseases; Genetic Marker; Genomics; Human Genetics; Inheritance; Locus; Marker; Microarrays; Mutant Allele; Mutation, Null; Neurogenetics; Non-Mendelian Inheritance; Pedigree Analysis; Protein Microarrays; QTL (Quantitative Trait Locus); QTL Mapping; Quantitative Genetics; Quantitative Inheritance; Quantitative Trait; RNA; Selective Breeding; Wild Type.
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Alcoholism
Further Reading Björk K, Hansson AC, and Sommer WH (2010) Genetic variation and brain gene expression in rodent models of alcoholism: Implications for medication development. International Review of Neurobiology 91: 129–171. Crabbe JC, Phillips TJ, and Belknap JK (2010) The complexity of alcohol drinking: Studies in rodent genetic models. Behavior Genetics 40: 737–750. Devineni AV and Heberlein U (2009) Preferential ethanol consumption in Drosophila models features of addiction. Current Biology 19: 2126–2132. Farris SP, Wolen AR, and Miles MF (2010) Using expression genetics to study the neurobiology of ethanol and alcoholism. International Review of Neurobiology 91: 95–128.
Phillips TJ, Belknap JK, Hitzemann RJ, et al. (2002) Harnessing the mouse to unravel the genetics of human disease. Genes, Brain and Behavior 1: 14–26. Spence JP, Liang T, Liu L, et al. (2009) From QTL to candidate gene: A genetic approach to alcoholism research. Current Drug Abuse Reviews 2: 127–134.
Relevant Websites http://www.ncbi.nlm.nih.gov – National Center for Biotechnology Information: Microarrays – Chipping away at the mysteries of science and medicine. http://www.niaaa.nih.gov – National Institutes of Health: National Institute on Alcohol Abuse and Alcoholism.
© 2013 Elsevier Inc. All rights reserved.
This article is a revision of the previous edition article by KE Browman, JC Crabbe, volume 1, pp 27–29, © 2001, Elsevier Inc.
Glossary Alcohol tolerance A diminished response to alcohol that may occur after previous exposure to alcohol. A larger dose of alcohol may be needed to produce the level of response seen after the initial exposure. Alcohol withdrawal Behavioral or physiological symptoms that may occur when exposure to alcohol is removed. Symptoms may include reduced activity levels, headache, and mild or severe seizures. Symptoms may be seen after an acute high dose of alcohol and increase in severity with more chronic alcohol exposure. Allele An alternative form of a gene. These are identified as different DNA sequences. Candidate gene A gene thought to influence a trait or disease. Case-control (candidate gene) study Comparisons of individuals with a particular disease (case) to those without the disease (control) for the frequency of a particular candidate gene allele. In a well-designed study, the cases and controls are matched on characteristics such
Clinical Findings Dependence on alcohol may include tolerance, withdrawal symptoms, and other severe medical consequences. Why do some individuals who engage in binge-like drinking at one stage of their lives manage ultimately to consume alcoholic beverages in moderation, while others develop significant and debilitating use disorders? The answer to this question is critical to prevention and treatment. Studies making use of compar isons between individuals who share many or few similar genes established the familial nature of alcoholism decades ago. Since that time, studies have been conducted in which a parti cular gene has been the focus and the frequency of that gene in alcohol-dependent individuals has been compared to its fre quency in nondependent individuals. Using this case-control method, evidence for the involvement of some genes in alcohol dependence, such as a dopamine receptor gene (DRD2), the dopamine transporter gene (SLC6A3/DAT1), the mu-opioid receptor gene (OPRM1), and a gamma-aminobutyric acid (GABA) receptor gene (GABARA2), among others, has been obtained, although results have sometimes appeared spurious or specific to particular populations. The most consistent find ing has been for the involvement of genes involved in alcohol metabolism, the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes. Certain variants of these genes have been known for many years to protect individuals from developing alcoholism, due largely to the aversive effects of increased levels in these individuals of one by-product of alco hol use, acetaldehyde.
62
as age, sex, socioeconomic status, educational level, and others. Genome-wide association study (GWAS) An examination of associations between genetic variants (alleles) across the entire genome and a disease trait. Knockout mouse A mouse in which a gene has been altered (knocked out) by genetic engineering, so that the gene no longer operates properly. Microarray Sometimes called a gene chip. A solid support (a membrane, glass or plastic slide) on which DNA sequences have been affixed and will interact (or hybridize) with specific sequences that may be found in brain or other biological samples. Fluorescent dyes are used to measure these interactions and provide a measure of gene expression. Quantitative trait locus (QTL) A gene at a particular location in the genome that influences the level of a quantitative trait. A quantitative trait is influenced by more than one gene; thus, a single QTL accounts for only some portion of the variation in that trait.
In addition to using alcohol dependence or alcoholism diag nosis as the trait in genetic analyses, human genetic studies have been conducted using frequency or amount of alcohol use and sensitivity to particular effects of alcohol, to categorize indivi duals and apply newer methods of genetic analysis. One such method is genome-wide association (GWAS). This method examines all or most of the genes that appear in different forms (genetic variants or alleles) in different individuals, in an attempt to identify those that are associated with alcoholism or with alcoholism-related traits. Individuals are often separated into cases and controls in this analysis. However, one important difference between this method and the case-control method described above is that this method does not limit the analysis to a specific candidate gene. Thus, GWAS has the potential for identifying novel genes and mechanisms that influence addic tion. The promising associations that have been found to date for various alcoholism-relevant phenotypes will require addi tional examination before definitive conclusions can be reached. Another sophisticated method is whole genome expression profiling. Rather than looking for differences in the form of a gene, this method examines differences in the amount of the gene’s coded information that is produced or expressed. This is done by using a microarray to determine gene expression level. A microarray is most commonly a glass or plastic slide on which different gene sequences have been placed that can interact with genetic material extracted from the brain or other biological samples. Gene expression has been compared between alcohol-dependent individuals and nondependent controls. Among the differences that have been found are differences in
Brenner’s Encyclopedia of Genetics, 2nd Edition, Volume 1
doi:10.1016/B978-0-12-374984-0.00028-0
Alcoholism the expression of genes important for glutamate functioning, a molecule that controls excitation in the brain. Differences have also been found in the expression of oligodendroglia-related genes that are important for the physical support of cells and for their appropriate functioning. Because brain samples are needed to perform expression profiling for central nervous system dis eases, these studies can only be performed using postmortem tissue. Therefore, one important question that remains unan swered is whether the differences existed before alcohol dependence developed or whether they are the result of excessive alcohol use. Both questions are important. Currently, many minds are working on the problem of cohesively analyzing the massive data sets from these different technologies to identify the brain gene networks that are important in alcoholism.
Findings from Animal Models Rodents have been particularly useful for studying traits that are thought to be relevant to human alcoholism. However, research in fruit flies (Drosophila melanogaster) and worms (Caenorhabditis elegans) have produced genetic results for alcohol effects, some of which are remarkably similar to those found in rodents and humans. Genetic similarity between mice and humans is about 80%. Therefore, genes of importance found in mouse studies can be identified and followed up in human studies, and vice versa. A particular advantage of collecting data in rodent models of human alcohol-related effects and problems is the ability to control alcohol exposure, environmental conditions during rear ing and in adulthood, and even genetic constitution. For example, the effects of several genes have been studied in mice by mutating the gene so that it no longer functions and then studying whether mice that have the mutant gene show a change in alcohol drinking or sensitivity. The mouse form of DRD2 (Drd2) has been studied in this way. Mice with the Drd2 gene have been compared to mutant mice (also called ‘knockout mice’) and have been found to drink less alcohol and show less preference for a place where they were previously given alcohol. These results, along with findings in human alcoholics, lend credence to a role for DRD2 in alcoholism. One method that can be used in animals, but not humans, is selective breeding. Individuals are chosen, for example, that show high levels of alcohol drinking and they are bred to each other to see if their offspring will also have a high level of drinking. Their level of drinking is compared to the offspring of mice that were produced by individual mice that did not drink much alcohol. In fact, these studies have shown that amount of alcohol consumed can be bred for, as can level of behavioral stimulation and level of behavioral sedation produced by alcohol. Several rat and mouse selected lines have been produced in this way and studied for genetic, biochemical, and other behavioral differences. For exam ple, neuropeptide Y (NPY), a natural substance that is produced in the brain and has long been known to stimulate eating, has been studied in lines of rats bred for high and low levels of alcohol drinking. Some drugs that block the NPY signal by keep ing it from binding to its receptor reduced alcohol drinking in an alcohol-preferring rat line. Recently, a study in nonhuman pri mates has supported a role for genetic variation in the NPY gene in susceptibility to heightened alcohol use following stress, and
63
there are promising data in human studies as well. Based on the convergent data, some clinical researchers are advocating combi nation therapies for alcoholism that include manipulation of NPY. Finally, a method called quantitative trait locus (QTL) map ping has been used to identify the chromosomal locations of genes that influence traits that are relevant to alcoholism. The alcohol responses of animals that are genetically different either throughout many parts of their genome, or just in one small region, are measured. Then, their response differences are compared to their genetic differences. The QTL analysis will detect whether a particular gene sequence or allele is present in individuals with high scores but mostly absent in individuals with low scores. This procedure was also used to study the severity of the behavioral reactions seen in mice when alcohol was taken away, or withdrawn, after they had been exposed to a high dose of alcohol. Whether the mice carried one allele or another for the gene, Mpdz, was found to be important for how severe the withdrawal reactions were. In several studies, it has been found that mice that have more severe alcohol withdrawal reactions are less likely to drink a lot of alcohol. Therefore, this gene may serve a protective role against high alcohol drinking and is being studied in humans.
Conclusions The last decade has seen advancements in technologies that have made it possible to go beyond the simple demonstration that alcoholism has a genetic component. Evidence from ani mal and human studies is converging on specific genes with roles in alcohol use disorders and their associations with spe cific biochemical pathways. Described herein is how genome-wide measures of genetic variants and of gene expres sion are being used to identify such genes. The identification of influential biochemical pathways is an important goal for the development of more effective medications for alcoholism.
Acknowledgements Supported by the Department of Veterans Affairs and NIH NIAAA grants P60AA010760 and U01AA016655.
See also: Additive Genetic Variance; Allele Frequency; Behavioral Genetics; Bioinformatics; Breeding of Animals; Candidate Gene; Centimorgan (cM); Chromosome Mapping; Complex Locus; Complex Traits; Continuous Variation; Deletion Mapping; Deletion Mapping, Mouse; Deletion Mutation; DNA Marker; DNA Sequencing; Gene; Gene Expression; Gene Frequency; Gene Mapping; Genetic Diseases; Genetic Marker; Genomics; Human Genetics; Inheritance; Locus; Marker; Microarrays; Mutant Allele; Mutation, Null; Neurogenetics; Non-Mendelian Inheritance; Pedigree Analysis; Protein Microarrays; QTL (Quantitative Trait Locus); QTL Mapping; Quantitative Genetics; Quantitative Inheritance; Quantitative Trait; RNA; Selective Breeding; Wild Type.
64
Alcoholism
Further Reading Björk K, Hansson AC, and Sommer WH (2010) Genetic variation and brain gene expression in rodent models of alcoholism: Implications for medication development. International Review of Neurobiology 91: 129–171. Crabbe JC, Phillips TJ, and Belknap JK (2010) The complexity of alcohol drinking: Studies in rodent genetic models. Behavior Genetics 40: 737–750. Devineni AV and Heberlein U (2009) Preferential ethanol consumption in Drosophila models features of addiction. Current Biology 19: 2126–2132. Farris SP, Wolen AR, and Miles MF (2010) Using expression genetics to study the neurobiology of ethanol and alcoholism. International Review of Neurobiology 91: 95–128.
Phillips TJ, Belknap JK, Hitzemann RJ, et al. (2002) Harnessing the mouse to unravel the genetics of human disease. Genes, Brain and Behavior 1: 14–26. Spence JP, Liang T, Liu L, et al. (2009) From QTL to candidate gene: A genetic approach to alcoholism research. Current Drug Abuse Reviews 2: 127–134.
Relevant Websites http://www.ncbi.nlm.nih.gov – National Center for Biotechnology Information: Microarrays – Chipping away at the mysteries of science and medicine. http://www.niaaa.nih.gov – National Institutes of Health: National Institute on Alcohol Abuse and Alcoholism.