Genome-wide epigenetic and gene expression profiles in psychiatric brains

Bowling K, Varley KE, Gertz J, Day K, Parker SL, Davis N, Waite LL, Absher D, Myers RM
Society for Neuroscience. 2011.


Although previous studies have aimed at identifying molecular mechanisms underlying psychiatric disorders such as schizophrenia, bipolar disorder and major depression, little is known about specific factors that contribute 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 in which environmental components contribute significantly. It has also been demonstrated 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. In order to better understand epigenetic contributions to psychiatric disorders, 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 for each disease. We are measuring DNA methylation in human post-mortem brain samples across three brain regions — dorsolateral prefrontal cortex, anterior cingulate cortex and nucleus accumbens from psychiatric affected individuals and unaffected controls. DNA methylation measurements have been taken at more than 600,000 CpGs throughout the genome using Reduced Representation Bisulfite Sequencing. Analysis of these measurements uncovered significant alterations 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 and in defining brain region function. Interestingly, we also observe brain-region specific cytosine methylation throughout the genome in the absence of CpG dinucleotide context. In addition, we have identified subtle changes in DNA methylation that associate with one or with all three psychiatric disorders. Some mental disorder associated methylation changes are brain region-specific while others are found across all three regions. Furthermore, using RNA-seq, we are sequencing messenger RNA from the same sample set to identify changes in gene expression that associate with each of the diseases as well as to determine functional relationships between aberrant DNA methylation and gene expression changes. The combination of epigenetic and gene expression measurements should help us better understand molecular differences underlying psychiatric disorders.