Cell-Type-Specific Methylome-wide Association Studies Implicate Neurotrophin and Innate Immune Signaling in Major Depressive Disorder

ABSTRACT Background We sought to characterize methylation changes in brain and blood associated with major depressive disorder (MDD). As analyses of bulk tissue may obscure association signals and hamper the biological interpretation of findings, these changes were studied on a cell-type-specific level. Methods In three collections of human postmortem brain (N=206) and one collection of blood samples (N=1,132) of MDD cases and controls, we used epigenomic deconvolution to perform cell-type-specific methylome-wide association studies (MWAS) within sub-populations of neurons/glia and granulocytes/T-cells/B-cells/monocytes for the brain and blood data, respectively. Sorted neurons/glia from a fourth post-mortem brain collection (N=58) were used for validation purposes. Results Cell-type-specific MWAS identified multiple findings in neurons/glia that were detected across brain collections and were reproducible in physically sorted nuclei. Cell-type-specific analyses in blood identified methylome-wide significant associations in T-cells, monocytes, and whole blood that replicated findings from a past methylation study of MDD. Pathway analyses implicated p75NTR/NGF signaling and innate immune TLR signaling in major depression. Top results in neurons, glia, bulk brain, T-cells, monocytes, and whole blood were enriched for genes supported by GWAS for MDD and other psychiatric disorders. Conclusions We both replicated and identified novel MDD-methylation associations in human brain and blood samples at a cell-type-specific level. Our results provide mechanistic insights into how the immune system may interact with the brain to affect MDD susceptibility. Importantly, our findings involved associations with MDD in human samples that implicated many closely related biological pathways. These disease-linked sites and pathways represent promising new therapeutic targets for MDD.