20151023A

Drug abuse is a serious public health problem that affects almost every community and family in some way. Each year drug abuse causes millions of serious illnesses or injuries among Americans. In recent years, it has become clear that there is a genetic basis of drug abuse – some people are much more in danger than others to become a drug addict. The National Institute on Drug Abuse (NIDA) has funded a large number of studies trying to elucidate the relationship between drug abuse and genes, both in humans and in laboratory animals.

In 2014, the NIDA center for GWAS in outbred rats (P50DA037844) has been founded that will apply cutting-edge genetic methods to elucidate the genetics of drug abuse-related behaviors in rats. This P-50 grant is titled “Integrated GWAS of complex behavioral and gene expression traits in outbred rats” and involves collaborators from the University of California in San Diego (Abraham Palmer) University of Michigan (Terry Robinson and Shelly Flagel),  SUNY Buffalo (Jerry Richards, Paul Meyer and Joe Lucke), University of Tennessee Health Sciences Center (Hao Chen) and Medical College of Wisconsin (Leah Solberg Woods).

The Center of Excellence focuses on quantitative genetic studies of a range of psychologically complex drug abuse related phenotypes in rats. The use of rats is critical to the center because many of the phenotypes we will study were developed using rats and have proven difficult or impossible to adapt for mice. Our center will utilize a unique rat population: the N/NIH heterogeneous stock (HS), which is derived from 8 fully sequenced inbred rat strains; this HS has been maintained as an outbred population for 65 generations. Outbred populations like the HS address a fundamental limitation of more traditional quantitative genetic studies, namely the inability to resolve quantitative trait loci (QTL) to regions that are small enough to permit identification of specific genes. Members of our center have unique expertise in the statistical techniques required to perform genome wide association studies (GWAS) in populations such as the HS in which individuals have varying degrees of close familial relationships to one another. Another technical strength of our center is the innovative use of a genotyping by sequencing (GBS) approach that allows us to obtain more than 100K informative single nucleotide polymorphisms (SNPs). Furthermore, we will concurrently use RNAseq to obtain genome-wide gene expression data that can be used to map expression QTLs (eQTLs). The identification of these eQTLs will significantly improve our ability to parse among the handful of candidate genes implicated by our behavioral QTLs. Finally, we have devised sophisticated and sensitive behavioral paradigms that allow us to phenotype important psychological traits in hundreds of rats per year, and obtain numerous high-quality quantitative behavioral measures. These measures have well-established relevance to addiction, and are the product of decades of research and expertise in the fields of experimental animal psychology and behavioral neuroscience. We present preliminary data clearly establishing the heritability and tractability of these traits. Because our studies will be performed in male and female rats, another major theme of our center is to explore sex differences at both the phenotypic and genetic levels. We will estimate the co-heritability between all behavioral traits, even those that are not measured in the same rats. Below, we outline the four research projects and four research cores that make up our proposed center. This center will create a national resource devoted to the genetic study of drug abuse related behavioral traits and will foster future research using HS rats and similar populations to study a variety of other medically important traits. The data we generate will foster unprecedented insights into the relationship between behavioral domains that influence the risk for drug abuse. Furthermore, it will identify specific genes, thus creating a unique opportunity to follow-up with hypothesis-driven studies. Finally, our center will also foster training of the next generation of drug abuse researchers, will enhance the training of the participating junior investigators, and will engage in outreach activities aimed at the broader public. If you would like to learn more about addiction, follow the links “Learn About Addiction” on our Education page (right sidebar).