National Institute on Alcohol Abuse and Alcoholism No. 60 July 2003 

The Genetics of Alcoholism 

Research has shown conclusively that familial transmission of alcoholism risk is at least in 

part genetic and not just the result of family environment (1). The task of current science is to 

identify what a person inherits that increases vulnerability to alcoholism and how inherited factors interact with the environment to cause disease. This information will provide the basis for 

identifying people at risk and for developing behavioral and pharmacologic approaches to prevent and treat alcohol problems. The advances being made now are built on the discovery 50 

years ago of the role in inheritance of DNA, the genetic material in cells that serves as a blueprint for the proteins that direct life processes. Alcoholism research, like other fields, is capitalizing on the scientific spinoffs of this milestone, among them the Human Genome Project and 

related efforts to sequence the genomes, the complete DNA sequences, of selected animals. 

A Complex Genetic Disease 

Studies in recent years have confirmed that identical twins, who share the same genes, are 

about twice as likely as fraternal twins, who share on average 50 percent of their genes, to 

resemble each other in terms of the presence of alcoholism. Recent research also reports 

that 50 to 60 percent of the risk for alcoholism is genetically determined, for both men and 

women (2–5). Genes alone do not preordain that someone will be alcoholic; features in the 

environment along with gene-environment interactions account for the remainder of the risk. 

Research suggests that many genes play a role in shaping alcoholism risk. Like diabetes 

and heart disease, alcoholism is considered genetically complex, distinguishing it from genetic 

diseases, such as cystic fibrosis, that result primarily from the action of one or two copies of a 

single gene and in which the environment plays a much smaller role, if any. The methods 

used to search for genes in complex diseases have to account for the fact that the effects of 

any one gene may be subtle and a different array of genes underlies risk in different people. 

Scientists have bred lines of mice and rats that manifest specific and separate alcoholrelated traits or phenotypes, such as sensitivity to alcohol’s intoxicating and sedative effects, 

the development of tolerance, the susceptibility to withdrawal symptoms, and alcohol-related 

organ damage (6,7). Risk for alcoholism in humans reflects the mix and magnitude of these 

and other phenotypes, shaped by underlying genes, in interaction with an environment in 

which alcohol is available. Genetic research on alcoholism seeks to tease apart the genetic 

underpinnings of these phenotypes and how they contribute to risk. 

One well-characterized relationship between genes and alcoholism is the result of variation 

in the liver enzymes that metabolize (break down) alcohol. By speeding up the metabolism of 

alcohol to a toxic intermediate, acetaldehyde, or slowing down the conversion of acetaldehyde to acetate, genetic variants in the enzymes alcohol dehydrogenase (ADH) or aldehyde 

dehydrogenase (ALDH) raise the level of acetaldehyde after drinking, causing symptoms that 

include flushing, nausea, and rapid heartbeat. The genes for these enzymes and the alleles, 

or gene variants, that alter alcohol metabolism have been identified. Genes associated with 

flushing are more common among Asian populations than other ethnic groups, and the rates 

of drinking and alcoholism are correspondingly lower among Asian populations (8,9). 

Alcohol Alert, a publication of 

the National Institute on Alcohol 

Abuse and Alcoholism, provides 

timely information on alcohol 

research and treatment to 

health professionals and other 

interested people. This issue is 

the sixtieth in the series. 

Research suggests that 

many genes play a role 

in shaping alcoholism 

risk. 

One well-characterized 

relationship between 

genes and alcoholism 

is the result of variation 

in the liver enzymes 

that metabolize (break 

down) alcohol. 

A Commentary by NIAAA Director, Ting-Kai Li, M.D...............................................................3 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 

Public Health Service • National Institutes of Health 
Genes, Behavior, and the Brain 

Addiction is based in the brain. It involves memory, motivation, and emotional state. The 

processes involved in these aspects of brain function have thus been logical targets for the 

search for genes that underlie risk for alcoholism. Much of the information on potential alcoholrelated genes has come from research on animals. Research has demonstrated a similarity 

in the mechanisms of many brain functions across species as well as an overlap between the 

genomes of animals—even invertebrates—and humans. 

One approach to identifying alcohol-related genes is to start with an aspect of brain chemistry on which alcohol is thought to have an impact, and work forward, identifying and manipulating the underlying genes and ultimately determining whether the presence or absence of 

different forms, or alleles, of a gene influence alcoholism risk. For example, genetic technology 

now permits scientists to delete or inactivate specific genes, or alternatively, to increase the 

expression of specific genes, and watch the effects in living animals. Because genes act in 

the context of many other genes, interpretation of these studies can be difficult. If one gene is 

disabled, for example, others may compensate for the loss of function. Alternatively, the loss 

of a single gene throughout development may be harmful or lethal. Nonetheless, these techniques can provide important clues to function. These approaches have been used to study 

how altering the expression of genes encoding the receptors (or their subunits) for neurotransmitters and intracellular messenger molecules alters the response to alcohol (10). 

Scientists also have an increasing array of methods for locating alcohol-related genes and 

gene locations and only then determining how the genes function, an approach known as 

reverse genetics. Quantitative trait loci (QTL) analysis seeks to identify stretches of DNA 

along chromosomes that influence traits, like alcohol sensitivity, that vary along a spectrum 

(height is another quantitative trait). QTLs have been identified for alcohol sensitivity, alcohol 

preference, and withdrawal severity (11). Ultimately, the goal is to identify and determine 

which candidate genes within the QTLs are responsible for the observed trait. Among the 

candidate genes already known to lie near alcohol-related QTLs are several that encode neurotransmitter receptors and neurotransmitters themselves. One of these, neuropeptide Y (NPY), 

lies within a QTL for alcohol preference in rats. NPY is a small protein molecule that is abundant 

in the brain and has been shown to influence the response to alcohol (12). 

Scientists also can scan the genome to identify genes whose activity differs among animals that respond differently to alcohol. The methods used are designed to measure the 

amount of messenger RNA which, as the first intermediary in the process by which DNA is 

translated into protein, is a reflection of gene expression. The advantage of this approach is 

its power to survey the activities of thousands of genes, some of which might not otherwise 

have been identified as candidates for involvement in alcohol-related behavior. Recent work 

in rats identified a gene that is differentially expressed in brain regions of alcohol-preferring 

rats and nonpreferring rats. The gene is within an already identified QTL for alcohol preference and codes for alpha-synuclein, a protein that has been shown to regulate dopamine 

transmission (13). 

Genetic Studies in Humans 

Knowledge gained from animal studies has assisted scientists in identifying the genes underlying brain chemistry in humans. Much research suggests that genes affecting the activity of 

the neurotransmitters serotonin and GABA (gamma-aminobutyric acid) are likely candidates 

for involvement in alcoholism risk. A recent preliminary study looked at five genes related to 

these two neurotransmitters in a group of men who had been followed over a 15-year period 

(14). The men who had particular variants of genes for a serotonin transporter and for one 

type of GABA receptor showed lower response to alcohol at age 20 and were more likely to 

have met the criteria for alcoholism. Another study found that college students with a particular variant of the serotonin transporter gene consumed more alcohol per occasion, more 

often drank expressly to become inebriated, and engaged more frequently in binge drinking 

than students with another variant of the gene (15). The relationships between neurotransmitter genes and alcoholism are complex, however; not all studies have shown a connection 

between alcoholism risk and these genes. 

Individual variation in response to stressors such as pain is genetically influenced and 

helps shape susceptibility to psychiatric diseases, including alcoholism. Scientists recently 

found that a common genetic variation in an enzyme (catechol-0-methyltransferase) that 

metabolizes the neurotransmitters dopamine and norepinephrine results in a less efficient 

Much of the information on potential 

alcohol-related genes 

has come from 

research on animals. 

Recent work in rats 

identified a gene that is 

differentially expressed 

in brain regions of 

alcohol-preferring rats 

and nonpreferring rats. 

Individual variation in 

response to stressors 

such as pain is genetically influenced and 

helps shape susceptibility to psychiatric 

diseases, including 

alcoholism. 

2
 
form of the enzyme and increased pain susceptibility (16). Scientists in another study found 

that the same genetic variant influences anxiety in women. In this study, women who had the 

enzyme variant scored higher on measures of anxiety and exhibited an electroencephalogram (EEG) pattern associated with anxiety disorders and alcoholism (17). 

The drug naltrexone has been shown to help some, but not all, alcohol-dependent patients 

reduce their drinking. Preliminary results from a recent study showed that alcoholic patients 

with different variations in the gene for a receptor on which naltrexone is known to act (the 

mu-opioid receptor) responded differently to treatment with the drug (18). This work demonstrates how genetic typing may in the future be helpful in tailoring treatment for alcoholism to 

each individual. 

NIAAA’s Collaborative Study on the Genetics of Alcoholism (COGA) is searching for alcoholrelated genes through studies of families with multiple generations of alcoholism. Using existing markers—known variations in the DNA sequence that serve as signposts along the length 

of a chromosome—and observing to what extent specific markers are inherited along with 

alcoholism risk, they have found “hotspots” for alcoholism risk on five chromosomes and a 

protective area on one chromosome near the location of genes for alcohol dehydrogenase 

(19). They have also examined patterns of brain waves measured by electroencephalogram. 

EEGs measure differences in electrical potential across the brain caused by synchronized 

firing of many neurons. Brain wave patterns are characteristic to individuals and are shaped 

genetically—they are quantitative genetic traits, varying along a spectrum among individuals. 

COGA researchers have found that reduced amplitude of one wave that characteristically 

occurs after a stimulus correlates with alcohol dependence, and they have identified chromosomal regions that appear to affect this P300 wave amplitude (20). Recently, COGA 

researchers found that the shape of a characteristic brain wave measured in the frequency 

stretch between 13 and 25 cycles per second (the “beta” wave) reflected gene variations at a 

specific chromosomal site containing genes for one type of GABA receptor (21). They suggest that this site is in or near a previously identified QTL for alcoholism risk. Thus, brain 

wave patterns reflect underlying genetic variation in a receptor for a neurotransmitter known 

to be involved in the brain’s response to alcohol. Findings of this type promise to help 

researchers identify markers of alcoholism risk and ultimately, suggest ways to reduce the 

risk or to treat the disease pharmacologically. 

Genetics Research—A Commentary by NIAAA Director, Ting-Kai Li, M.D. 

Even from the first drink, individuals differ substantially in their response to alcohol. Genetics 

research is helping us understand how genes shape the metabolic and behavioral response 

to alcohol and what makes one person more vulnerable to addiction than another. An understanding of the genetic underpinnings of alcoholism can help us identify those at risk and, in 

the long term, provide the foundation for tailoring prevention and treatment according to the 

particular physiology of each individual. 

References 

(1) National Institute on Alcohol Abuse and Alcoholism (NIAAA). The Genetics of 

Alcoholism. Alcohol Alert No. 18. Rockville, MD: NIAAA, 1992. (2) Heath, A.C.; Bucholz, K.K.; 

Madden, P.A.F.; et al. Genetic and environmental contributions to alcohol dependence risk in a 

national twin sample: Consistency of findings in women and men. Psychological Medicine 

27:1381–1396, 1997. (3) Heath, A.C., and Martin, N.G. Genetic influences on alcohol consumption patterns and problem drinking: Results from the Australian NH&MRC twin panel follow-up 

survey. Annals of the New York Academy of Sciences 708:72–85, 1994. (4) Kendler, K.S.; 

Neale, M.C.; Heath, A.C.; et al. A twin-family study of alcoholism in women. American Journal of 

Psychiatry 151:707–715, 1994. (5) Prescott, C.A., and Kendler, K.S. Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins. 

American Journal of Psychiatry 156:34–40, 1999. (6) Crabbe, J.C. Alcohol and genetics: New 

models. American Journal of Medical Genetics (Neuropsychiatric Genetics) 114:969–974, 2002. 

(7) Tabakoff, B., and Hoffman, P.L. Animal models in alcohol research. Alcohol Research & 

Health 24(2):77–84, 2000. (8) Li, T.K. Pharmacogenetics of responses to alcohol and genes 

that influence alcohol drinking. Journal of Studies on Alcohol 61:5–12, 2000. (9) Makimoto, K. 

Drinking patterns and drinking problems among Asian-Americans and Pacific Islanders. Alcohol 

Health & Research World 22(4):270–275, 1998. (10) Bowers, B.J. Applications of transgenic 

and knockout mice in alcohol research. Alcohol Research & Health 24(3):175–184, 2000. (11) 

Crabbe, J.C.; Phillips, T.J.; Buck, K.J.; et al. Identifying genes for alcohol and drug sensitivity: 

Recent progress and future directions. Trends in Neurosciences 22(4):173–179, 1999. (12) 

Pandey, S.C.; Carr, L.G.; Heilig, M.; et al. Neuropeptide Y and alcoholism: Genetic, molecular, 

NIAAA’s Collaborative 

Study on the Genetics 

of Alcoholism (COGA) 

is searching for alcoholrelated genes through 

studies of families with 

multiple generations of 

alcoholism. 

Brain wave patterns 

reflect underlying 

genetic variation in a 

receptor for a neurotransmitter known to 

be involved in the 

brain’s response to 

alcohol. 

3
 
and pharmacological evidence. Alcoholism: Clinical and Experimental Research 27:149–154, 2003. (13) Liang, T.; Spence, J.; Liu, 

L.; et al. α-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and 

nonpreferring rats. Proceedings of the National Academy of Sciences of the U.S.A. 100(8):4690–4695, 2003. (14) Schuckit, M.A.; 

Mazzanti, C.; Smith, T.L.; et al. Selective genotyping for the role of 5-HT2A, 5-HT2C, and GABAα6, receptors and the serotonin transporter in the level of response to alcohol: A pilot study. Biological Psychiatry 45:647–651, 1999. (15) Herman, A.I.; Philbeck, J.W.; 

Vasilopoulos, N.L.; and Depetrillo, P.B. Serotonin transporter promoter polymorphism and differences in alcohol consumption behaviour in a college student population. Alcohol and Alcoholism 38:446–449, 2003. (16) Zubieta, J.-K.; Heitzeg, M.M.; Smith, Y.R.; et al. 

COMT val158met genotype affects μ-opioid neurotransmitter responses to a pain stressor. Science 299:1240–1243, 2003. (17) 

Enoch, M.A.; Xu, K.; Ferro, E.; et al. Genetic origins of anxiety in women: A role for a functional catechol-O-methyltransferase polymorphism. Psychiatric Genetics 13(1):33–41, 2003. (18) Oslin, D.W.; Berrettini, W.; Kranzler, H.R.; et al. A functional polymorphism 

of the μ-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology 

28:1546–1552, 2003. (19) Edenberg, H.J. The collaborative study on the genetics of alcoholism: An update. Alcohol Research & 

Health 26(3):214–217, 2002. (20) Begleiter, H.; Porjesz, B.; Reich, T.; et al. Quantitative trait loci analysis of human event-related 

brain potentials: P3 voltage. Electroencephalography and Clinical Neurophysiology 103(3):244–250, 1998. (21) Porjesz, B.; Almasy, 

L.; Edenberg, H.J.; et al. Linkage disequilibrium between the beta frequency of the human EEG and a GABAA receptor gene locus. 

Proceedings of the National Academy of Sciences of the U.S.A. 99:3729–3733, 2002. 

Full text of this publication is available on NIAAA’s World Wide Web site at 

http://www.niaaa.nih.gov 

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