An analysis that compared the DNA of drug abusers with that of non-abusing controls has identified 89 genes that are likely to contain variants that contribute to addiction vulnerability.

Background: Vulnerability to addiction is a complex trait with strong genetic influences. Since the mid-1990s, scientists have been developing methods and tools to identify and evaluate the functional role of genes and their variants. The impact of such efforts has been greatly enhanced by the Human Genome and International HapMap Projects. By 2001, the first low-resolution genome-wide association studies from the NIDA-IRP’s Molecular Neurobiology Branch were published. Genetic research technology is now able to reliably scan the genome of individuals for genetic variants linked to specific functions.

Study Design: From 1990 to 2005, thousands of people participated in studies at NIDA-IRP’s Molecular Neurobiology Branch, providing self-reports and DSM Diagnostic Interview Schedule scores. From among this pool, researchers
identified 980 African-American and European-American “drug abusers” (heavy lifetime use of illegal substances) and 740 controls (no significant history of addictive substances, no abuse, no dependence). Pooled DNA samples, prepared from
blood extracted from each group were used to examine a panel of close to 640,000 genetic variations.

What They Found: Using strong statistical models that focused on the overlaps between the samples, this screen identified 89 genes that display clusters of genetic variants that are likely involved in addiction vulnerability. Most of these genes are expressed in the brain. Twenty-one of these genes influence cell adhesion, and nearly all of those are expressed in brain regions implicated in memory processes.

Comments from the Authors: The nature of the addiction-associated genes identified in this study, especially those involved in cell adhesion, suggest the critical role played by dysfunctional nerve cell connections in the addicted brain.

What’s Next: Other genes that emerged from the analysis are being tested in the context of where they are located in the brain and their likely functions: enzymes, transporters, receptors, protein processing, and transcriptional regulation. Results
like these highlight characteristics that are common to human addiction and may facilitate efforts to develop targeted prevention and treatment strategies.

Publication: The study, led by Drs. George Uhl and Qing-Rong Liu of the Molecular Neurobiology Branch at the National Institutes of Health Intramural Research Program at NIDA in Baltimore, was published in volume 141B, pages 1-8 (2006) of
the American Journal of Medical Genetics Part B (Neuropsychiatric Genetics).

NIDA NewsScan, August 22, 2007

Epigenetics involves the transmission of information from a cell or multicellular organism to its descendants without that information being encoded in the chemicals that make up the DNA of a particular gene. Neuroscientists are beginning to investigate these mechanisms in neurobiological processes. These processes include memory, behavior, and long-lasting nervous system changes, such as those that result from drug abuse.

Two NIDA scientists - Dr. Christine Colvis and Dr. Jonathan Pollock - and their colleagues explain some of the latest research in this area in a review article that captures information presented at a special symposium at the 2005 annual meeting of the Society for Neuroscience. They describe new research in which:

• scientists show the effects of gene-environment interactions and how nurturing in early development can affect adult behavior;
• researchers uncover mechanisms involving the consolidation of short-term memory to long-term memory;
• certain protein-enzyme interactions may assist scientists in developing new drugs for a variety of degenerative diseases of the nervous system; and
• cocaine affects biochemical activity related to a specific protein and how these changes differ in acute versus chronic abuse.

What it means: Epigenetics involves new concepts and new ways of thinking about fundamental processes that influence highly complex nerve functions, including those involved in the behavioral and biochemical aspects of drug abuse and addiction. These new paradigms may offer new avenues for therapy.

Dr. Colvis and Dr. Pollock, both at NIDA, published their review in the November 9, 2005 issue of the Journal of Neuroscience.

NIDA NewsScan, February 1, 2006

Drug abuse has a strong hereditary component; however, new research suggests genetics and shared environment have little impact when it comes to selecting a particular illegal drug.

Scientists interviewed 1,196 male twin pairs about their history of use, abuse, and/or dependence on marijuana, sedatives, stimulants, cocaine, opiates, hallucinogens, inhalants, and over-the-counter medications. Subjects in the study ranged from 20 to 58 years old.

Upon analyzing data from the interviews the scientists could find no evidence that shared genetic or environmental factors increased the risk of abusing one specific illegal drug over another. The decision to use and abuse a specific drug seemed to depend on unshared factors, such as ease of access.

What it means: The findings suggest that the search for genetic variations that affect human drug abuse should focus on factors that increase or decrease the risk of abuse of all types of illegal substances, not just a specific drug.

Dr. Kenneth Kendler and colleagues from the Medical College of Virginia, Virginia Commonwealth University in Richmond published this research in the April 2003 issue of the American Journal of Psychiatry.

NIDA NewsScan, July 30, 2003

Results of a genome-wide search, or “genome scan,” by a team of researchers led by Dr. George Uhl, from the National Institute on Drug Abuse (NIDA) in Baltimore, Maryland, provide the first evidence that specific regions of the human genome differ between abusers of illegal drugs and nonabusers. The findings of Dr. Uhl and his colleagues are an important step toward identifying genes that affect a person’s vulnerability or resistance to substance abuse, and offer hope for identifying individuals at high risk for addiction and matching abusers with the most effective treatments.

The researchers looked for differences in the frequency of 1,494 genetic variants known as SNPs (single nucleotide polymorphisms, or “snips”) between DNA samples from 667 unrelated individuals with a history of heavy drug use and 338 individuals with no significant lifetime use of any addictive substance (controls). Using the SNP markers, whose locations in the genome are known, the research team identified more than 40 regions across the genome that differ between drug abusers and controls in DNA samples from both European Americans and African Americans. Eight of these regions previously have been linked to alcohol or nicotine dependence, suggesting that genes in these regions contribute to individual vulnerability to abuse of multiple substances.

Studies have shown that genetic factors account for about half of human drug abuse vulnerability (environmental factors account for the other half),

but researchers have not yet identified the individual genes that are involved. “Once you identify the genes, then you can ask, ‘What part does this specific gene play in the overall drug abuse problem?’” Dr. Uhl says.

He hopes this research will provide “knowledge about this genetic half of the problem that we can use to better match the preventions and the treatments to the people who are most likely to benefit from them.”

What it means: Scientists have known that genetic factors play a role in determining a person’s vulnerability to substance abuse. The findings of this study identify specific regions of the human genome that may be involved, narrowing the search for genes that make a person more or less susceptible to addiction. Identifying these genes will shed light on the mechanisms of addiction and may make it possible to target treatments and prevention efforts to those individuals most likely to benefit.

The study by Dr. George Uhl, Dr. Qing-Rong (Tim) Liu, Ms. Donna Walther, and Ms. Judith Hess of the NIDA Intramural Research Program, and Dr. Daniel Naiman of the Johns Hopkins University appears in the December issue of the American Journal of Human Genetics.

NIDA NewsScan, January 3, 2002

The age at which an individual takes his/her first drink is strongly predictive of a broad range of future problem behaviors, including alcoholism, abuse of illicit drugs, conduct and antisocial personality disorders, nicotine addiction, underachievement in school, and poorimpulse control, according to researchers from the University of Minnesota.

The head of the Minnesota research team, Dr. Matt McGue, says the team's findings indicate that there may be a common genetic basis for a number of behavioral problems, and an early age for the first use of alcohol could be a "marker" for a genetic risk for these problems.

The researchers also found that early use of alcohol tends to run in families, and, at least in males, it is an inheritable trait. There were

significantly more conduct disorders and other behavioral problems in the sons than in the daughters of parents whose age at first drink came before age 15. For girls, shared environmental factors, rather than age at first drink, appeared to be more of a determining factor.

What it means: Age at first drink may prove to be helpful in identifying teens who are at risk for future substance abuse and other problems, permitting them to be targeted for early, intensive prevention and intervention programs.

The research is published as two separate papers in the August 15, 2001 issue of Alcoholism: Clinical and Experimental Research.

NIDA NewsScan, October 16, 2001