Alcohol Research: Current Reviews

g ations translate into altered biological biology, which allows for analyses of enetic factors determine a substanfunction. Much of this work involves entire gene networks, may help tial portion of a person’s risk for genetically engineering animal models researchers elucidate the genetic basis alcoholism. Drs. Tatiana Foroud and in which individual genes are deleted of complex traits, such as alcoholism, Tamara J. Phillips summarize some of or inactivated, if possible, restricting both in humans and in animal models. the approaches that have been used to gene alterations to certain tissues or The use of high-throughput technologies determine the magnitude of the overdevelopmental periods, report Drs. for molecular profiling enables researchers all genetic contribution to alcohol dependence in specific populations Matthew T. Reilly, R. Adron Harris, to identify novel gene–gene interacand identify particular genes involved. and Antonio Noronha. Together with tions and describe gene networks Traditional approaches in humans high throughput genetic engineering that may shed new light on the proinclude linkage analyses, case–control and genome sequencing strategies that cesses involved in the development studies, and genome-wide association draw at least in part on community-wide of alcoholism. (pp 306–317) studies. Approaches using animal modresources, these strategies hopefully els of human alcoholism have focused will lead to additional breakthroughs The Impact of gene–environment on targeted breeding strategies and the in understanding the genetic basis of Interaction on Alcohol Use Disorders generation of animals in which spealcoholism. (pp 282–291) here are three different gene– cific genes are deleted or inactivated. Tenvironment interactions—the Most recently, investigators are using epigenetics—Beyond the additive model, the “fan-shaped” approaches analyzing the genetic basis genome in Alcoholism

g ations translate into altered biological biology, which allows for analyses of enetic factors determine a substanfunction. Much of this work involves entire gene networks, may help tial portion of a person's risk for genetically engineering animal models researchers elucidate the genetic basis alcoholism. Drs. Tatiana Foroud and in which individual genes are deleted of complex traits, such as alcoholism, Tamara J. Phillips summarize some of or inactivated, if possible, restricting both in humans and in animal models. the approaches that have been used to gene alterations to certain tissues or The use of high-throughput technologies determine the magnitude of the overdevelopmental periods, report Drs. for molecular profiling enables researchers all genetic contribution to alcohol dependence in specific populations Matthew T. Reilly, R. Adron Harris, to identify novel gene-gene interacand identify particular genes involved. and Antonio Noronha. Together with tions and describe gene networks Traditional approaches in humans high throughput genetic engineering that may shed new light on the proinclude linkage analyses, case-control and genome sequencing strategies that cesses involved in the development studies, and genome-wide association draw at least in part on community-wide of alcoholism. (pp 306-317) studies. Approaches using animal mod-resources, these strategies hopefully els of human alcoholism have focused will lead to additional breakthroughs The Impact of gene-environment on targeted breeding strategies and the in understanding the genetic basis of Interaction on Alcohol Use Disorders generation of animals in which spe-alcoholism. (pp 282-291) here are three different genecific genes are deleted or inactivated.

Tenvironment interactions-the
Most recently, investigators are using epigenetics-Beyond the additive model, the "fan-shaped" approaches analyzing the genetic basis genome in Alcoholism P interaction, and the crossover interacof alcoholism at the level of the entire rocesses that modify gene expres-tion. In this article, Drs. Danielle M. genome, thus moving beyond analyses sion without altering the underly-Dick, and Kenneth S. Kendler discuss of the roles of individual genes in the ing DNA sequence (i.e., epigenetic what is known about gene-environment development alcoholism. (pp 266-272) processes) contribute to a person's pre-interactions in the field of alcohol use disposition to alcoholism, report Mr.
disorders and the challenges in inter-

Identifying genetic Variation for
Bela G. Starkman and Drs. Amul J. preting these three types of interactions.

Alcohol Dependence
Sakharkar and Subhash C. Pandey.
(pp 318-324) r esearchers use a wide range of anal-For example, these processes modify yses to identify the genes involved the proteins with which the DNA Bridging Animal and human in the development of alcoholism and binds in the cell, thereby making the models: Translating From their specific roles in this process. In DNA more or less accessible to the (and to) Animal genetics this article, Drs. Arpana Agrawal and enzymes that are involved in gene expression. Methylation of the DNA S tudying both humans and animal Laura J. Bierut discuss the advantages also can interfere with gene expres-models is necessary to fully underand limitations of these approaches, explore the role of such genetic studies sion. The authors describe several stand the neurobiology of alcoholism examples of how these and other from the molecular to the cognitive of alcoholism in the context of other coexisting diseases (e.g., esophageal epigenetic mechanisms influence level, including issues such as alcohol cancer), and suggest additional steps the expression of genes related to withdrawal severity, sensitivity to alcoholism. (pp 293-305) rewards, impulsivity, and dysregulated such as the development of large-scale research consortia, that can help enhance alcohol consumption. In this article, the success of genetic studies and, ulti-Ms. Amanda M. Barkley-Levenson Identifying gene Networks mately, gain new insight into potential and Dr. John C. Crabbe discuss how Underlying the Neurobiology treatment approaches. (pp 274-282) the use of animal models, such as of ethanol and Alcoholism A rodents, nonhuman primates, and lthough many DNA regions and even invertebrates, allows for a degree Using genetically engineered genes have been identified that of genetic and environmental control Animal models in the may be associated with alcoholism, that would not be possible in human Postgenomic era to Understand researchers have not been able to place studies. By using these species to recagene Function in Alcoholism A these genes in any kind of biological pitulate discrete aspects of alcohol use fter identifying numerous genetic context that would explain the under-disorders as they appear in human variations that underlie the complex lying functional biology. According to populations, researchers are able to C u r r e n t R e v i e w s

Development of Alcoholism:
implicated in the risk for alcoholism (i.e., the circadian system), with the An overview encompasses genes that encode recep-circadian system influencing alcohol A tors for the signaling molecule (i.e., use patterns and alcohol consumption wide range of experimental neurotransmitter) γ-aminobutyric altering circadian functions. Several approaches have been used to acid (GABA). According to Drs. "clock genes" contribute to the circaidentify genes contributing to the Cecilia M. Borghese and R. Adron dian system, whose activities are development of alcohol dependence.
Harris, considerable evidence points tightly controlled. In this article, Dr. In this article, Dr. Howard J. Edenberg to the GABAA receptor as one of the Dipak K. Sarkar explores why the cirreviews some of these strategies as well main targets of alcohol; and DNA cadian system is vulnerable to alcohol as some of the genes that have been variations (i.e., polymorphisms) in toxicity and describes the complex implicated in alcoholism risk based the genes encoding this receptor have interactions between the circadian on findings from these studies. These been linked with alcohol dependence. system, the stress response, and alcohol include genes encoding enzymes The authors posit that analysis of the consumption. For example, alcoholinvolved in alcohol metabolism, specific gene variants for the GABA A mediated modulation of clock genes the receptor for the brain signaling receptor may be a first step in match-may help modulate the activity of the molecule (i.e., neurotransmitter) ing alcohol-dependent patients with body's stress response system, which γ-aminobutyric acid (GABA), proteins appropriate pharmacotherapy. (pp in turn may increase the propensity involved in the circadian rhythm, and 345-353) to drink alcohol following a stressful proteins involved in immune responses, event. (pp 362-366) all of which will be explored in more Immune Function genes, detail in subsequent articles in this genetics, and the Neurobiology Discovering genes Involved in issue. (pp 336-338) of Addiction Alcohol Dependence and other T Alcohol responses: role of he immune system and those parts genes encoding enzymes Animal models of the nervous system that regulate Involved in ethanol metabolism immune responses play a role in the m any genes play a role in the devel-T he genes that encode the main development of addictions, particularly opment of alcohol dependence. enzymes involved in ethanol in the context of stressful situations. However, these genes do not explain Both stress and alcohol exposure can all the genetic variance associated with metabolism, alcohol dehydrogenase activate certain cells of the nervous alcoholism, and systematic approaches (ADH) and aldehyde dehydrogenase system, resulting in the induction of to gene discovery are critical to identify (ALDH), influence a person's risk of genes involved in innate immune novel genes and mechanisms involved alcoholism. Both enzymes are encoded responses, particularly inflammatory in alcohol dependence. Drs. Kari J. by several genes, some of which exist reactions. According to Dr. Fulton T. Buck, Lauren C. Milner, Deaunne L. in different variants that influence the Crews, one pivotal component of this Denmark, Seth G.N. Grant, and Laura rate of ethanol and acetaldehyde process is a regulatory protein called B. Kozell describe efforts using animal metabolism. Drs. Thomas D. Hurley NF-κB, which is regulated by both models for identifying specific alcoholand Howard J. Edenberg describe stress and alcohol. Alcohol-related related traits and that have resulted in specific variants in both ADH-and induction of innate immune genes the identification of DNA regions, ALDH-encoding genes that alter in certain brain regions can contribute quantitative trait genes (QTGs), and ethanol metabolism in a way which to alcohol's effects by disrupting the high-quality QTG candidates as well as impacts the drinker's risk of alcoholism decision-making processes and inducing their plausible mechanisms of action. as well as of associated conditions, negative emotions as well as impact These animal-derived DNA loci and such as esophageal cancer. (pp alcohol drinking behavior. (pp QTGs may be relevant to alcoholism 339-344) 355-361) risk in humans. (pp 367-374)