The proportion of neuronal cells in a given brain region influences the identification of differentially methylated regions. (a) Whole-tissue methylation signals show false-positive brain-region differences. Panel shows a plot of smoothed methylation signals from sorted neuronal and glial cells (teal and purple lines) from DLPFC and HF (solid and dashed lines) as well as from whole-tissue DLPFC (gold line) and HF (grey line). (b) Estimated neuronal fraction of cells for whole-tissue samples differs between DLPFC and HF (mean DLPFC = 0.53 (n = 19), mean HF = 0.30 (n = 13), two-sample t-test P value 6.3 × 10-6). (c) Estimated neuronal fraction of cells for whole-tissue samples using universal DMRs vs. estimated neuronal fraction using brain region-specific DMRs from DLPFC (gold), HF (grey), and STG (blue).