Genetic studies of neuropsychiatric disorders, behaviour, specific cognitive processes, and learning and memory

The focus of my research is the genetic study of behaviour, specific aspects of cognition, and psychiatric and neurological disorders for which a genetic predisposition has been established, including attention-deficit hyperactivity disorder, childhood-onset anxiety disorders, childhood-onset depression, reading disabilities, and Tourette syndrome.

Numerous studies have implicated an imbalance in the neurotransmitter systems or neurological development for these disorders. We are able to test specific genes from these systems by screening these genes for DNA changes that may contribute to the genetic predisposition.

We have identified a number of genes contributing to these disorders and molecular studies are in progress to understand the relationship of DNA variation in these genes to the development of the disorder. For example, we identified two novel genes as associated to ADHD and reading disabilities respectively. Both of these genes were identified based on their location in regions linked to ADHD and reading disabilities. To date there is little or no information about the expression or biological function of these proteins. Our prediction is that both of these genes are involved in neuronal outgrowth and cell migration based on the presence of protein domains that have been shown to be involved in these processes. Through collaboration with Philippe Monnier, we are beginning the characterization of these two genes by examining the expression pattern during development using a chick embryo model, followed by functional tests of the role of these proteins in neuronal outgrowth/migration.

For complex traits, it has been predicted that changes in gene expression are more likely to contribute to disease susceptibility than changes in the code for the protein sequence. For a number of the genes we have identified as susceptibility genes, we have ruled out changes in the coding region as contributing to risk, thus we are now searching for the regions that control gene regulation. We collaborated with Dr. Rod Bremner to create genome-wide maps of gene regulatory elements (funding from The Krembil Scientific Development Seed Fund). Current studies are now focused on determining the impact of DNA variation in these regulatory regions using high-throughput methods to test thousands of regions and the DNA variants within them simultaneously.

In developing humans and other mammals, not all genes are created equal or equally used. The expression of certain genes, known as imprinted genes, is determined by just one copy of the parents genetic contribution. In humans, there are at least 80 known imprinted genes. If a copy of an imprinted gene fails to function correctly or if both copies are expressed the result can be a variety of heritable conditions, such as Prader-Willi and Angelman syndromes, or increased risk for cancer.

To study the mechanism of imprinted genes in mouse brain, we collaborated with Dr. Bing Ren (UCSD) generating a whole-genome, base-resolution map of allelic DNA methylation in the frontal cortex (The Krembil Scientific Development Seed Fund). The study identified many genomic regions that are differentially methylated, dependent on the parent-of-origin. We discovered sequence signatures correlated with CG methylation that are evolutionarily conserved as well as previously unknown genes that are subject to imprinting, including micro RNAs.

The most surprising finding was significant amounts of methylation outside of the CG dinucleotide context (non-CG) in the brain. This epigenetic mark previously documented only in embryonic stem cells, preimplantation embryos and oocytes, was thought to be a marker of pluripotency. The significance of non-CG methylation is unknown, however the presence of this mark in brain is very specific, suggesting that it correlates with an important biological function (Cell 148(4): 816-831, 2012).

For a list of Dr. Barr's publications, please visit PubMed, Scopus or ORCID.

Professor, Department of Psychiatry, University of Toronto
Senior Scientist, Neurosciences & Mental Health Program, The Hospital for Sick Children