10.1517/14622416.5.8.1037 © 2004 Future Medicine Ltd ISSN 1462-2416 Pharmacogenomics (2004) 5(8), 1037–1048 1037 R EVIEW For reprint orders, please contact: reprints@futuremedicine.com Alcoholism: genes and mechanisms Gabor Oroszi MD, PhD & David Goldman MD † † Author for correspondence † Laboratory of Neurogenetics, NIAAA, NIH, 5625 Fishers Lane, Room 3S32, MSC9412, Rockville, MD 20852, USA Tel: +1 301 443 0059; Fax: +1 301 480 2839; E-mail: dgneuro @box-d.nih.gov Keywords: alcoholism, ADH, ALDH, COMT, GABA Aα6 , genetics, HT TLPR, NPY, OPRM1, treatment response Alcoholism is a chronic relapsing/remitting disease that is frequently unrecognized and untreated, in part because of the partial efficacy of treatment. Only approximately one- third of patients remain abstinent and one-third have fully relapsed 1 year after withdrawal from alcohol, with treated patients doing substantially better than untreated [1]. The partial effectiveness of strategies for prevention and treatment, and variation in clinical course and side effects, represent a challenge and an opportunity to better understand the neurobiology of addiction. The strong heritability of alcoholism suggests the existence of inherited functional variants of genes that alter the metabolism of alcohol and variants of other genes that alter the neurobiologies of reward, executive cognitive function, anxiety/dysphoria, and neuronal plasticity. Each of these neurobiologies has been identified as a critical domain in the addictions. Functional alleles that alter alcoholism- related intermediate phenotypes include common alcohol dehydrogenase 1B and aldehyde dehydrogenase 2 variants that cause the aversive flushing reaction; catechol-O- methyltransferase (COMT) Val158Met leading to differences in three aspects of neurobiology: executive cognitive function, stress/anxiety response, and opioid function; opioid receptor μ1 (OPRM1) Asn40Asp, which may serve as a gatekeeper molecule in the action of naltrexone, a drug used in alcoholism treatment; and HTTLPR, which alters serotonin transporter function and appears to affect stress response and anxiety/dysphoria, which are factors relevant to initial vulnerability, the process of addiction, and relapse. Alcoholism is a classic pharmacogenomic disease in the obvious sense that the intake of a drug is essential to the onset and perpetuation of the ill- ness, and because alcoholism, like certain other substance dependencies (nicotine and opioid addiction), is moderately to highly heritable. Large, methodologically sound studies in twins, buttressed by family and adoption studies, have revealed that alcoholism is more than 50% herit- able. The inherited vulnerability is both sub- stance-specific and nonspecific [2], as well as both pharmacokinetic (involving differences in drug absorption, distribution, and metabo- lism) and pharmacodynamic (involving differ- ences in drug response). The challenge for the genetics of alcoholism is to identify functional genetic variants that confer vulnerability or protection. A somewhat overlapping task is to define those polymorphisms that influence the response of an alcoholic to treatment, affecting efficacy or compliance. Genetic polymorphisms known or predicted to affect the risk for alcoholism or individual response to treatment highlight pharmaco- kinetic and pharmacodynamic mechanisms but are only examples of the promise of functional genes in alcoholism. The importance of other polymorphisms is not excluded, and because there are many routes to alcoholism vulnerabil- ity and many pathways to recovery, it is antici- pated that many genetic loci will play a role. T he reader is also referred to recent compre- hensive reviews that more completely describe, and reference, particular areas; for example, the role of genetic variation in dopamine receptors in humans [3,4] and candidate gene identifica- tion in animal models [5]. T his paper focuses on common functional variations in humans and mechanisms by which these variations mediate vulnerability. Genes and mechanisms Two intermediate phenotypes (mediating traits) or endophenotypes (heritable intermediate phenotypes) that are predictive of the develop- ment of alcoholism are the alcohol-induced flush- ing reaction and acute level of response (LR) to alcohol. Alcohol-induced flushing is an aversive response to alcohol that is common among Ori- entals, and may include cutaneous flush, increased skin temperature, decreased blood pres- sure, tachycardia, dizziness, anxiety, nausea, head- ache, and generalized weakness [6]. T he flushing reaction is protective against alcoholism. LR to