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

Chan, R. F.; Turecki, G.; Shabalin, A. A.; Guintivano, J.; Zhao, M.; Xie, L. Y.; van Grootheest, G.; Kaminsky, Z. A.; Dean, B.; Penninx, B. W. J. H.; Aberg, K. A.; van den Oord, E. J. C. G.

doi:10.1101/432088

bioRxiv · 10.1101/432088

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

Chan, R. F.·Turecki, G.·Shabalin, A. A.·Guintivano, J.·Zhao, M.·Xie, L. Y.·van Grootheest, G.·Kaminsky, Z. A.·Dean, B.·Penninx, B. W. J. H.·Aberg, K. A.·van den Oord, E. J. C. G.

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Abstract

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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Chan, R. F., Turecki, G., Shabalin, A. A., Guintivano, J., Zhao, M., Xie, L. Y., van Grootheest, G., Kaminsky, Z. A., Dean, B., Penninx, B. W. J. H., Aberg, K. A., van den Oord, E. J. C. G.. 2018-10-03. Cell-type-specific methylome-wide association studies implicate neurodegenerative processes and neuroimmune communication in major depressive disorder. https://doi.org/10.1101/432088

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