About half of a person's risk for drug dependence resides in his or her genes, with the rest attributable to circumstantial and environmental factors. Genes influence vulnerability to drug abuse by affecting personality traits, physiological responses to drugs, frequency of drug use, and the neurobiological mechanisms of learning, memory, and behavior.
NIDA funds a robust research portfolio to identify the genes and genetic processes responsible for these effects. The ultimate objective is to uncover information and mechanisms that can be exploited to improve and personalize prevention and treatment of drug abuse and addiction.
NIDA's Genetics Workgroup is charged with overseeing and monitoring these efforts. Led by Dr. Jonathan Pollock, chief of NIDA's Genetics and Molecular Neurobiology Research Branch, the Workgroup comprises approximately 20 scientists representing all NIDA divisions. They meet monthly to review developments in the field and identify needs and opportunities for further research, then issue calls for grant proposals on promising approaches.
A Workgroup subcommittee, the NIDA Genetics Coordinating Committee (NGCC), oversees all genetic research involving human subjects, ensuring that it is designed to answer important questions and takes full advantage of collaborative opportunities within NIDA and with other parts of the National Institutes of Health (NIH). The NGCC, chaired by Dr. Joni Rutter, associate director of human population and applied genetics for the Division of Basic Neuroscience and Behavioral Research, also coordinates the work of the NIDA Genetics Consortium. This is a group of approximately two dozen investigators who conduct human subject studies.
Under an agreement with NIDA and NIH, Consortium scientists contribute blood and DNA samples collected during research, as well as clinical data, to an NIH repository; in exchange, they receive access to the repository's extensive collection. Scientists outside the Consortium can also gain access to the collection if they agree to share their own samples and data. The repository, which is located at Rutgers University's Center for Genetic Studies, has a collection of over 40,000 human DNA samples. Information on ongoing studies and data from completed studies can be found at the Center's Web site (https://genetics.rutgers.edu/).
Stages of Gene Identification
The initial clue that some of the risk for drug abuse and addiction is inherited was the observation that the problems tend to run in families. NIDA-funded twin studies added support for the idea, by showing that siblings who share more genes are more alike in terms of developing or not developing a drug disorder. High-risk genes may make individuals more likely to experiment with drugs or susceptible to drug effects that promote addiction. Some high-risk genes may only manifest under certain conditions, such as familial abuse or neglect.
Early projects initiated and overseen by the Workgroup included studies of genes related to biological pathways known to play roles in drug addiction, such as the nicotine receptor and the dopaminergic neurotransmitter system. Comparisons of addicted versus nonaddicted individuals implicated specific DNA variations within such genes.
Researchers also studied genetically engineered animals to examine how their behavior changed when particular genes were turned off. For example, a NIDA-funded study found that disrupting a mouse's Clock gene increased its propensity to self-administer cocaine and seek out new experiences ("Manic Mice Show Heightened Sensitivity to Rewards").
Although research on single genes has yielded important information, complex brain disorders such as substance abuse and addiction likely reflect convergent effects of many genes. New technologies are being exploited to identify these genes and the ways their combinations and interactions may alter risk. The Workgroup is fostering research and analytic methodologies that capitalize on ongoing NIH-wide efforts such as the International HapMap Project (see hapmap.ncbi.nlm.nih.gov) and the 1000 Genomes Project (see www.genome.gov/27528684 and www.1000genomes.org).
Many projects apply the powerful technique of genome-wide association (GWA) scanning. Researchers simultaneously test thousands of individuals' DNA for hundreds of thousands of genetic variants that may correlate to drug abuse. "Through GWA studies, we are finding associations with specific genetic variants. Now, we need to understand their functions," says Dr. Rutter. This work is facilitated by databases that compile findings from many investigations of specific genes, their functions, and their links to disease (see www.ncbi.nlm.nih.gov/gene).
For example, researchers are using GWA and other methods to compare the genetic profiles of smokers who have become dependent on nicotine with the profiles of those who have not. Of particular interest is a family of genes that determine the structure and functions of nicotinic acetylcholine receptors, to which nicotine attaches to produce many of its effects ("Studies Link Family of Genes to Nicotine Addiction").
| Research Question | Examples of Approach |
|---|---|
| Does a particular trait have a genetic component? | Twin studies |
| Where in the genome are the genes that influence the trait? | Genetic marker study Genome-wide association study |
| What specific genes are involved? | Candidate gene study Fine mapping |
| How does the gene influence the organism? | Knock-out gene study |
| Does variation in the gene influence human health? | Clinical study |
| How does epigenetics influence gene expression? | DNA methylation Chromatin modification |
The Workgroup also funds studies on the related topic of epigenetics. Virtually every cell in the body contains the same genes, but the epigenome determines which genes are active in each cell at each moment in time. Chemical changes, such as methylation, determine the epigenome. Dr. Rutter uses a computer as an analogy: "The DNA is equivalent to the hardware and the epigenome is akin to the software because it acts on top of the DNA to dictate changes in gene expression." She says, "If we can better understand how epigenetic changes take place, we can create better treatment approaches."
Sharing for Outreach and Economy
The Genetics Workgroup's mission includes keeping scientists up-to-date on advances in genetics as they apply to drug abuse. For example, last year the group sponsored a week-long course that drew 80 researchers from approximately 40 universities to learn about recent findings in the genetics of addiction. "The course introduced addiction researchers who lacked genetic expertise to experts in the field of genetics of addiction," says Dr. Pollock, who organized the program. "It provided a networking opportunity for both the instructors and the participants."
In July 2009, the Workgroup sponsored the travel of nine junior investigators to the 50th Annual Short Course on Medical and Experimental Mammalian Genetics at the Jackson Laboratory in Bar Harbor, Maine.