ARRA IMPACT REPORT:
Genetics/Epigenetics of Addiction
Public Health Burden
The risk and trajectory of drug addiction is determined by multiple interacting genes and environmental factors. Furthermore, many of the genes that affect addiction risk can be directly influenced by environmental factors that can in turn lead to persistent chemical modifications (epigenetic marks) on their target genes. To alleviate the exorbitant costs (roughly $600 billion a year) associated with drug addiction in our Nation, we must explore and better characterize these complex interactions to inform the development of targeted prevention and treatment interventions.
Much of the research to identify genetic and epigenetic determinants of addiction risk is done in animals. A variety of ARRA-funded grants tap into these models to identify new or verify suspected candidates:
Gene Expression Differences and Addiction Risk: Smoking usually begins during adolescence, but the likelihood of its leading to addiction varies from person to person. Researchers from the University of Tennessee examined inbred Lewis and Fisher 344 rat strains that differ greatly in their drug self-administration habits (Lewis having high and Fisher 344 having low tendency to self-administer drugs, including nicotine). The analysis uncovered significant gene expression differences that contribute to differences in the propensity for initiating and continuing voluntary nicotine intake in adolescent rats. The results reveal 38 differentially expressed genes, related to synaptic plasticity, signaling, and gene transcription in GABAergic neurons that are likely to influence substance abuse behaviors. The differential pattern of gene expression in GABAergic neurons in Lewis rats may predispose them for their characteristic drug seeking behavior. Extending this work to humans, by focusing on similar genetic differences between smokers vs. non-smokers, could be an important step towards the development of early prevention and the design of more effective treatments.1
Genetics and Sensitivity to Psychostimulants and Opiods: Using mouse models, researchers at the University of Chicago sought to identify chromosomal regions containing genes that influence sensitivity to psychostimulants and opioids. They also studied the effects of variations in these genes in response to amphetamine in healthy human volunteers. The study shows that variations in the Csnk1e gene were associated with differences in sensitivity to methamphetamine and fentanyl, suggesting it to be a modulator of the response to psychostimulants and opioids. These differences in response are important for determining a person’s risk for substance abuse and may provide the basis for the design of more effective substance abuse/addiction prevention and treatment approaches.2
Human Genetic and Genomic Studies of Risk
Studies are currently under way to examine the genetic (and epigenetic) factors contributing to a range of addictions, including critical public health problems like smoking, which are so costly to this country. New approaches use emerging technologies to map and characterize inherited and drug-induced alterations in the human brain.
Improving Genetic Models of Substance Abuse Disorders: Researchers at the Washington University School of Medicine hypothesized that incorporating age at onset of regular smoking (AOS) into gene association analyses could bolster gene discovery efforts and our ability to predict risk of nicotine dependence. They analyzed over 3,369 single nucleotide polymorphisms (SNPs) – each SNP represents a difference in a single DNA building block, called a nucleotide - from 349 candidate genes, applying the SNP x AOS interaction models, which resulted in higher numbers of nominally significant tests when compared to main effect models. Some previously strong SNPs showed an even greater fit to this interaction model. Additionally, some SNPs not previously registered as significant hits were among the strongest candidates identified, including SNPs located in GRIN2B, which encodes a subunit of N-methyl-D-aspartate receptor channel involved in age-related synaptic plasticity. The results of this study highlight the importance of adding a more textured definition of substance abuse related behavioral traits into genetic models of substance use disorders, because they can boost the sensitivity, reliability, and confidence of genetic association studies in drug abuse research.3
Technology advances: Developing Tools and Mapping Networks
New high-throughput technologies are allowing researchers to amass vast quantities of information, which when combined with new bioinformatics tools to analyze the data will provide critical new insights and point to novel medication targets for addiction. ARRA-funded grants will advance the development of supportive technologies and resources:
Development of a Nicotine Behavioral Assay in Zebrafish: Investigators at the University of Minnesota and the Mayo Clinic have developed a nicotine behavioral assay in zebrafish, an emerging vertebrate model system for understanding the genetics of behavior, to study the response to nicotine in genetically altered wild-type animals and strains. Genes were altered using a method (transposon mutagenesis) that generates mutant genes that can then be deactivated. Using this method, they identified two mutations associated with an altered nicotine response. Since the mutations have known human counterparts, they represent potential targets for developing new diagnostic kits and/or cessation medications. This zebrafish mutagenesis approach, in the context of behavioral testing, provides a powerful platform for investigating the contribution of genetic variation to vulnerability to drug addiction and other psychiatric disorders.4
Development of Genetically Diverse Mouse Strain: Researchers at the Jackson Laboratory in Bar Harbor, Maine, have developed a new mouse strain that is more genetically diverse than any other mouse population. The genetic diversity of this resource will enable more complex trait analyses to be conducted in mice to better keep pace with rapid developments in human genetic studies. For example, the researchers were able to map a blood cholesterol trait to a tiny region on chromosome 3 containing only 11 protein-coding genes and reduce the pool of candidate SNPs in this region from 32,196 to 7. Diversity Outbred mice, used in concert with the Collaborative Cross strain, could accelerate discovery of the genetic basis for disease and may have other applications, including screening during drug development for rare genetically based adverse effects.5
Contributing NIH Institutes & Centers
- National Institute on Drug Abuse (NIDA)