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Cell-type-specific methylome-wide association studies implicate neurodegenerative processes and neuroimmune communication in major depressive disorder

By Robin F. Chan, Gustavo Turecki, Andrey A. Shabalin, Jerry Guintivano, Min Zhao, Lin Y Xie, Gerard van Grootheest, Zachary A Kaminsky, Brian Dean, Brenda W.J.H. Penninx, Karolina A. Aberg, Edwin J.C.G. van den Oord

Posted 03 Oct 2018
bioRxiv DOI: 10.1101/432088

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<1x10-5) 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 <1x10-5), 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.

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