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Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD study.

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Smith, R. G. | Pishva, E. | Kouhsar, M. | Imm, J. | Dobricic, V. | Johannsen, P. | Wittig, M. | Franke, A. | Vandenberghe, R. | Schaeverbeke, J. | Freund-Levi, Y. | Frölich, L. | Scheltens, P. | Teunissen, C. E. | Frisoni, G. | Blin, O. | Richardson, J. C. | Bordet, Regis | Engelborghs, S. | de Roeck, E. | Martinez-Lage, P. | Altuna, M. | Tainta, M. | Lleó, A. | Sala, I. | Popp, J. | Peyratout, G. | Winchester, L. | Nevado-Holgado, A. | Verhey, F. | Tsolaki, M. | Andreasson, U. | Blennow, K. | Zetterberg, H. | Streffer, J. | Vos, S. J. B. | Lovestone, S. | Visser, P. J. | Bertram, L. | Lunnon, K.

Edité par CCSD ; Alzheimer's Association / Wiley -

International audience. INTRODUCTIONWe investigated blood DNA methylation patterns associated with 15 well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration.METHODSWe assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease (EMIF-AD) study using the EPIC array.RESULTSWe identified Bonferroni-significant differential methylation associated with CSF YKL-40 (five loci) and neurofilament light chain (NfL; seven loci) levels, with two of the loci associated with CSF YKL-40 levels correlating with plasma YKL-40 levels. A co-localization analysis showed shared genetic variants underlying YKL-40 DNA methylation and CSF protein levels, with evidence that DNA methylation mediates the association between genotype and protein levels. Weighted gene correlation network analysis identified two modules of co-methylated loci correlated with several amyloid measures and enriched in pathways associated with lipoproteins and development.DISCUSSIONWe conducted the most comprehensive epigenome-wide association study (EWAS) of AD-relevant CSF biomarkers to date. Future work should explore the relationship between YKL-40 genotype, DNA methylation, and protein levels in the brain.

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