DNA methylation in the human frontal cortex reveals a putative mechanism for age-by-disease interactions

A consistent gene set undergoes age-associated expression changes in the human cerebral cortex, and our Age-by-Disease Model posits that these changes contribute to psychiatric diseases by "pushing" the expression of disease-associated genes in disease-promoting directions. DNA methylation (DNAm) is an attractive candidate mechanism for age-associated gene expression changes. We used the Illumina HumanMethylation450 array to characterize genome-wide DNAm in the postmortem orbital frontal cortex from 20 younger (<42 years) and 19 older (>60 years) subjects. DNAm data were integrated with existing normal brain aging expression data and sets of psychiatric disease risk genes to test the hypothesis that age-associated DNAm changes contribute to age-associated gene expression changes and, by extension, susceptibility to psychiatric diseases. We found that age-associated differentially methylated regions (aDMRs) are common, robust, bidirectional, concentrated in CpG island shelves and sea, depleted in CpG islands, and enriched among genes undergoing age-associated expression changes (OR = 2.30, p = 1.69 × 10^-27). We found the aDMRs are enriched among genetic association-based risk genes for schizophrenia, Alzheimer's disease (AD), and major depressive disorder (MDD) (OR = 2.51, p = 0.00015; OR = 2.38, p = 0.036; and OR = 3.08, p = 0.018, respectively) as well as expression-based MDD-associated genes (OR = 1.48, p = 0.00012). Similar patterns of enrichment were found for aDMRs that correlate with local gene expression. These results were replicated in a large publically-available dataset, and confirmed by meta-analysis of the two datasets. Our findings suggest DNAm is a molecular mechanism for age-associated gene expression changes and support a role for DNAm in age-by-disease interactions through preferential targeting of disease-associated genes.