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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 (&lt;42 years) and 19 older (&gt;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\u2009=\u20092.30, <jats:italic>p<\/jats:italic>\u2009=\u20091.69\u2009\u00d7\u200910<jats:sup>\u221227<\/jats:sup>). We found the aDMRs are enriched among genetic association-based risk genes for schizophrenia, Alzheimer\u2019s disease (AD), and major depressive disorder (MDD) (OR\u2009=\u20092.51, <jats:italic>p<\/jats:italic>\u2009=\u20090.00015; OR\u2009=\u20092.38, <jats:italic>p<\/jats:italic>\u2009=\u20090.036; and OR\u2009=\u20093.08, <jats:italic>p<\/jats:italic>\u2009=\u20090.018, respectively) as well as expression-based MDD-associated genes (OR\u2009=\u20091.48, <jats:italic>p<\/jats:italic>\u2009=\u20090.00012). 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.<\/jats:p>","DOI":"10.1038\/s41398-019-0372-2","type":"journal-article","created":{"date-parts":[[2019,1,29]],"date-time":"2019-01-29T17:05:10Z","timestamp":1548781510000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["DNA methylation in the human frontal cortex reveals a putative mechanism for age-by-disease interactions"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0663-7569","authenticated-orcid":false,"given":"Brandon C.","family":"McKinney","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chien-Wei","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanbin","family":"Rahman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyunjung","family":"Oh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3225-6778","authenticated-orcid":false,"given":"David A.","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Tseng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Etienne","family":"Sibille","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,1,29]]},"reference":[{"key":"372_CR1","unstructured":"The Global Burden of Disease: 2004 Update. www.who.int\/healthinfo\/global_burden_disease\/GBD_report_2004update_full.pdf. 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