TY - JOUR T1 - Cell-type-specific methylome-wide association studies implicate neurodegenerative processes and neuroimmune communication in major depressive disorder JF - bioRxiv DO - 10.1101/432088 SP - 432088 AU - Robin F. Chan AU - Gustavo Turecki AU - Andrey A. Shabalin AU - Jerry Guintivano AU - Min Zhao AU - Lin Y Xie AU - Gerard van Grootheest AU - Zachary A. Kaminsky AU - Brian Dean AU - Brenda W.J.H. Penninx AU - Karolina A. Aberg AU - Edwin J.C.G. van den Oord Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/10/03/432088.abstract N2 - We studied the methylome in three collections of human postmortem brain (N=206) and blood samples (N=1,132) of subjects with major depressive disorder (MDD) and controls. Using an epigenomic deconvolution approach we performed cell-type-specific methylome-wide association studies (MWAS) within sub-populations of neurons/glia and granulocytes/T-cells/B-cells/monocytes for bulk brain and blood data, respectively. Multiple MWAS findings in neurons/glia replicated across brain collections (ORs=509-538, P-values<1×10−5) and were reproducible in an array-based MWAS of sorted neurons/glia from a fourth brain collection (N=58). Pathway analyses implicated p75NTR/VEGF signaling, neurodegeneration, and blood-brain barrier perturbation. Cell-type-specific analysis in blood identified associations in CD14+ monocytes -- a cell type strongly linked to neuroimmune processes and stress. Top results in neurons/glia/bulk and monocytes were enriched for genes supported by GWAS for MDD (ORs=2.02-2.87, P-values=0.003 to <1×10−5), neurodegeneration and other psychiatric disorders. In summary, we identified novel MDD-methylation associations by using epigenomic deconvolution that provided important mechanistic insights for the disease. ER -