Eric J. Vallender, PhD

Associate Director for Research

As with any complex human disease, understanding the genomic underpinnings associated with psychiatric disease has been difficult. Animal models can be especially useful when the biology and molecular etiology is strongly conserved and extreme environmental heterogeneity among human users is particularly confounding. Through this work we have identified genetic variation which, while not sharing an evolutionary origin, functionally act in parallel manners in non-human primates and humans. We have also explored conservation and divergence in genes associated with psychiatric disorders. Most recently we have begun exploring brain transcriptomics across species and phenotypes.

Understanding the evolution of the human brain and associated behavior is critical for illuminating the origins of neuropsychiatric diseases, human behavior, and characteristics which make us uniquely human. Using comparative genetic and genomic techniques it is possible to identify and characterize the important genetic differences between species. In doing so we hope to understand the genetic changes that have led to the emergence of the human brain and human-specific behaviors and to better interpret human pathologies in this context. Our ongoing studies have identified correlations between evolutionary changes associated with the emergence of the human brain and neurodevelopmental disorders including schizophrenia and autism. We are pursuing this for identifying causes and improving understandings of these diseases.

In the post-genomic era we are quickly being inundated with association studies tying genetic polymorphisms with measures of disease. Our work focuses on a core challenge; clarifying the mechanisms by which genotype leads to a diseased phenotype. Currently, we focus on G-protein coupled receptors, proteins associated with a number of diseases and major drug targets. We have characterized the effects of genetic variation on the ligand binding and intracellular signaling of the mu-opioid receptor. We have further established the association between this genetic variation and alcohol abuse, cortisol levels, and other behavioral phenotypes. Finally, we have demonstrated how this variation mediates the efficacy of naltrexone, a drug used in the treatment of alcoholism and other addictions and less commonly for other psychiatric disorders.

The development of improved animal models and usage of animals in biomedicine can be facilitated by comparative information on genotype/phenotype associations of the animal model and the human disease. Animal models are primarily useful if they replicate human disease and response. If the phenotype of the animal model is similar to the human phenotype, but the genetic underpinnings diverge, then the research will be of reduced translational value. Using comparative genetics, we aim to highlight animal models likely to have translational validity and to strengthen and improve the models, improving the power of animal studies and maximizing their utility. Our studies have identified naturally-occurring variation which both models disease phenotypes of interest and which may have confounding effects on animal research. These have improved animal allocation and directly contributed to improved study design.