Elucidating the role of DNA methylation in psychiatric disorders.

K. Bowling; K.E. Varley; J. Gertz; K. Day; S.L. Parker; L.L. Waite; D.E. Absher; R.M. Myers
Society for Neuroscience. 2010.


Extensive research efforts have been undertaken to identify mechanisms underlying psychiatric disorders including schizophrenia, bipolar disorder and major depression, yet little remains known about specific factors contributing to these mental illnesses. While genetic alterations have been shown to play a role in psychiatric phenotypes, these disorders exhibit discordance between monozygotic siblings and a non-Mendelian pattern of inheritance, suggesting that psychiatric disorders are complex behavioral traits and that environmental components contribute significantly. It has also been shown that environmental factors induce epigenetic changes that may disrupt mental health. Therefore, it is imperative that the epigenetic contribution to psychiatric illness be carefully explored. To this end, we are assaying DNA methylation on a genome-wide scale to determine whether altered epigenetic patterns are found in psychiatric disorders, and to identify potential biomarkers of each disease. We are assaying DNA methylation in post-mortem brain samples across three regions - dorsolateral prefrontal cortex, anterior cingulate cortex and nucleus accumbens (n = 24 for control samples and each psychiatric illness) from individuals with these disorders and unaffected control individuals. We are assaying DNA methylation status across 27,000 CpGs and covering over 14,000 genes in each brain sample with the Illumina Infinium Methyl 27 platform, and assaying DNA methylation signatures at more than 500,000 CpGs throughout the genome with Reduced Representation Bisulfite Sequencing. Preliminary analysis of these measurements indicates strong changes in DNA methylation between the three brain regions regardless of psychiatric disorder status, suggesting that DNA methylation is involved in brain region-specific gene regulation. We have also found DNA methylation changes that associate with either one or with all three psychiatric disorders. Some changes are brain region-specific while others are found in all three regions. The genes nearby methylation changes are involved in a variety of cellular processes, which suggests that there are multiple affected pathways. We are also sequencing mRNA from the same sample set to identify mis-regulated gene expression associated with each of the diseases as well as determine the functional relationships between aberrant DNA methylation and gene expression changes. The combination of epigenetic and gene expression measurements should help us understand molecular differences underlying psychiatric disorders.