Large segments of our population use tobacco, alcohol, and other drugs. Cigarette smoking is common in both industrialized and developing countries. In the United States, over 43 million people use tobacco, and worldwide, over one billion people are tobacco users (Centers for Disease Control, 2010
; World Health Organization, 2010
). In the U.S., over 400,000 people die every year from tobacco related illnesses, and smoking remains the greatest contributor to preventable death (Mokdad et al., 2004
). With increasing tobacco use in developing countries, it is predicted that the worldwide death toll will rise to eight million people per year by 2030. Alcohol is the most commonly used and abused substance in the population, and 12.5% of adults in the U.S. develop alcohol dependence during their lifetime (Hasin et al., 2007
). In 2004, the World Health Organization estimated that alcohol use disorders affected 76.3 million people globally (World Health Organization, 2004
). In the U.S., almost 80,000 people die per year from the consequences of alcohol consumption, which includes alcohol related illnesses and accidents (Mokdad et al., 2004
). Our society pays a high price for substance use, primarily through increased health care costs and judicial system expenditures. It is estimated that over 11% of federal and state government budgets ($374 billion in 2005) are spent dealing with the consequences of tobacco, alcohol, and other substance use, abuse, and dependence (The National Center on Addiction and Substance Abuse at Columbia University, 2009
The development of addiction requires the use of a substance and a subsequent chain of behavioral events that leads to addiction. The key steps in the development of addiction include the initiation of substance use, the conversion from experimental use to established use, and finally the development of addiction (see ). Each step is influenced by environmental and genetic factors, some of which are common to all steps, and others that are specific. For example, environmental factors, such as the availability of nicotine, alcohol, and drugs, play a role in each stage in the development of addiction, but accessibility of a substance is relatively more important in the initiation of substance use. Similarly, high cost of a substance through taxation can reduce initiation, use, and addiction; however taxation has a stronger influence on teenagers who have less money, thus limiting initial use. Family, twin, and adoption studies also convincingly demonstrate a substantial genetic contribution to the development of addiction to nicotine, alcohol, and illicit drugs. Heritability estimates for nicotine, alcohol, and drug addiction are in the range of 50% to 60% (Heath et al., 1997
; Tsuang et al., 1998
; Kendler et al., 2003
; Li, 2006
). In general, it appears that environmental factors have a stronger effect on initiation, whereas genetic factors play a larger role in the transition from regular use to the development of addiction (Vink et al., 2005
). Given the robust behavioral evidence for the role of genetic influence in addiction, genetic studies are warranted.
Steps in the development of dependence.
Initial inroads into understanding the genetic influences of addiction in humans relied on both genetic linkage mapping and candidate gene association studies, resulting in the identification of hundreds of potential genes contributing to the addiction process. Yet, few of these associations have been replicated in independent studies, potentially reflecting a number of false positives and/or genetic heterogeneity in which multiple genes contribute modest effects. The last decade, however, has seen a revolution in genetic technologies so that hundreds of thousands of genetic variants (or single nucleotide polymorphisms; SNPs) can be queried in thousands of individuals in a cost effective manner. This technology facilitates genome wide association studies (GWAS) that test for an association of genetic variants with an illness in order to discover genetic contributions to complex diseases. Complex diseases are caused by many genetic and environmental factors working together, and GWAS has permitted the discovery of hundreds of genetic variants that alter the risk of developing multiple complex diseases, including type 2 diabetes, Crohn's disease, and Parkinson's disease (Hindorff et al., 2010
). More recently, the genetic tools of GWAS have been applied to the study of addiction to identify genetic variations that contribute to this illness. The success of this approach has been in part due to the creation of genetic research consortia for the study of nicotine and illicit drugs (NIDA Genetics Consortium http://www.nida.nih.gov/about/organization/genetics/consortium/index.html
) and alcohol (e.g. NIAAA's Collaborative Study on the Genetics of Alcoholism; COGA; http://www.niaaa.nih.gov/ResearchInformation/ExtramuralResearch/SharedResources/projcoga.htm
) permitting the collection of the massive numbers of comprehensively assessed subjects and DNA samples required for large scale studies. These resources are also shared with the scientific community though the database of Genotypes and Phenotypes (dbGaP http://www.ncbi.nlm.nih.gov/gap
) so that scientists around the world can test new hypotheses about the genetic underpinnings of addiction.
This review will give a synopsis of the current understanding of genetic contributions to the vulnerability of substance dependence. There have been extensive discussions about the terminology used to define substance use disorder – “dependence” versus “addiction.” Substance dependence is the official diagnostic nomenclature used in the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 2000) to represent the syndrome of substance misuse that leads to adverse consequences and includes a cluster of symptoms such as tolerance, withdrawal, and inability to stop using (See DSM-IV substance dependence for the complete diagnostic criteria). The creators of DSM-IV criteria selected the term “dependence” because of the concern of stigmatization associated with “addiction.” At this time, revisions to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) are underway for release in 2013. In this revision, issues have again been raised about the term used to define this clinical syndrome. In order to differentiate from the normal physiologic development of tolerance and withdrawal that develops with substance use from the compulsive drug use with loss of control, DSM-5 proposes the use of the word “addiction” to define substance use disorder. The words “dependence“ and “addiction” are used interchangeably in this review to represent the same underlying concept of substance use disorder.