Leaping over the blood-brain barrier: DNA methylation as a link between peripheral and central immune systems

The majority of existing DNA methylation (DNAm) studies have used peripheral surrogate tissues to research molecular mechanisms underlying brain-related traits. Epigenetic processes in the brain have yet to be fully elucidated by DNAm findings from peripheral tissues, as these processes are complex to disentangle from DNAm tissue- and cell type-specificity. Furthermore, distinct brain cell types play important roles in brain health and disease. Building on previous findings of high blood-brain correlations at some DNAm sites, we specifically aimed to 1) identify single DNAm sites associated with DNAm-estimated brain cell type proportions in both the frontal brain and peripheral blood, 2) to combine blood DNAm sites to predict brain cell type proportions through multivariate models, and 3) to examine the role of biological factors associated with blood DNAm, age and epigenetic age acceleration (EAA) on brain cell type proportions. Epigenome-wide association studies for seven distinct estimated brain cell type proportions in matched frontal brain and peripheral blood samples (n=104) revealed that [~]7% of brain cell type-associated DNAm sites had correlating DNAm levels in peripheral blood (p<0.05). Six DNAm sites in peripheral blood were associated with endothelial and stromal brain cell type proportions (False Discovery Rate<0.05). Brain cell type proportion predictions trained with machine learning approaches using peripheral blood DNAm showed a correlation (p<0.05) with microglia and astrocyte proportions estimated through cell deconvolution using brain DNAm. Estimated blood immune cell type proportions were significantly associated with estimated brain cell type proportions. Lastly, brain EAA was associated with different brain and blood cell types proportions (p<0.05). These results show that DNAm levels in peripheral blood can inform brain cell type proportions, even though DNAm patterns are tissue-specific. The correlations between DNAm profiles specific to immune cell types in blood and brain highlights the link between the peripheral immune system and immune functions in the central nervous system.