Psychiatric disorders such as major depressive disorder (MDD) are complex diseases where negative
stressors increase the likelihood of its onset through epigenetic changes, such as DNA methylation (DNAm).
Presently, disease-associated DNAm patterns of MDD have not been fully elucidated. This is in part due to the
reliance of peripheral tissues such as blood, buccal cells, and saliva where it is unknown how DNAm changes
from these tissues might be an accurate reflection of those changes in the brain. As such, there is an urgent
need to provide a comprehensive database that would cross-compare DNAm patterns between the brain and
other peripheral tissues to highlight candidate regions where disease-associated DNAm can be observed. To
this end, our overall goal is to establish a comprehensive epigenomic database where DNAm patterns can be
cross-compared between key brain regions (e.g., the hippocampus, amygdala, and dorsolateral prefrontal
cortex), their neurons and glia components, and peripheral tissues. Our central hypothesis is that disease-
associated DNAm will more likely reside in regions that vary in DNAm between different tissues. Our specific
aims will address the following questions: In Aim 1, DNAm will be evaluated at a genome-wide level and cross-
compared between brain and peripheral tissues to identify regions which have varying DNAm between tissues.
In Aim 2, we will expand DNAm assessment in neuron and glia to the aforementioned key brain regions
involved in MDD and compare that with peripheral tissues. In Aim 3, disease-associated DNAm regions will be
evaluated using pathology-archived brain tissues from 206 MDD cases and 206 matched controls. This is the
largest post-mortem study of MDD that specifically evaluates DNAm. Disease-associated DNAm will be
overlaid with tissue-specific DNAm to determine regions where MDD-associated DNAm patterns will likely to
occur. This proposed study is significant as it will provide a comprehensive epigenetic database that will guide
researchers to candidate regions and suitable peripheral tissues to investigate DNAm changes in MDD. Its use
may also be extended to other psychiatric disorders. This proposed study is innovative as it uses fresh brain,
neuron, glia and peripheral tissues from the same individual to establish an epigenome database. It also uses
disease-associated DNAm identified from a large cohort of post-mortem MDD brains to identify regions that are
“hot-spots” for disease-associated methylation changes.