Journal Article

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

Richardson, Jill C., Streffer, Johannes, Frisoni, Giovanni, Engelborghs, Sebastiaan, Vos, Stephanie J. B., Peyratout, Gwendoline, Freund‐Levi, Yvonne, Teunissen, Charlotte E., Nevado‐Holgado, Alejo, Lunnon, Katie, Smith, Rebecca G., Sala, Isabel, Johannsen, Peter, Dobricic, Valerija, Frölich, Lutz, Lleó, Alberto, Tsolaki, Magda, Blin, Olivier, Verhey, Frans, Roeck, Ellen, Andreasson, Ulf, Bordet, Régis, Schaeverbeke, Jolien, Zetterberg, Henrik, Kouhsar, Morteza, Franke, Andre, Bertram, Lars, Imm, Jennifer, Altuna, Miren, Visser, Pieter Jelle, Martinez‐Lage, Pablo, Winchester, Laura, Blennow, Kaj, Pishva, Ehsan, Wittig, Michael, Tainta, Mikel, Vandenberghe, Rik, Popp, Julius, Lovestone, Simon, Scheltens, Philip

2024

Overview

INTRODUCTION We investigated blood DNA methylation patterns associated with 15 well‐established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration. METHODS We assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease (EMIF‐AD) study using the EPIC array. RESULTS We 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. DISCUSSION We 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. Highlights Blood DNA methylation was assessed in the EMIF‐AD MBD study. Epigenome‐wide association studies (EWASs) were performed for 15 Alzheimer's disease (AD)–relevant cerebrospinal fluid (CSF) biomarker measures. Five Bonferroni‐significant loci were associated with YKL‐40 levels and seven with neurofilament light chain (NfL). DNA methylation in YKL‐40 co‐localized with previously reported genetic variation. DNA methylation potentially mediates the effect of single‐nucleotide polymorphisms (SNPs) in YKL‐40 on CSF protein levels.

• Publisher: John Wiley & Sons, Inc,Alzheimer's Association / Wiley,John Wiley and Sons Inc
• Subject: Aged / Alzheimer Disease - blood / Alzheimer Disease - cerebrospinal fluid / Alzheimer Disease - genetics / Alzheimer's disease / Alzheimer's disease (AD) / amyloid / Biological markers / biomarker / Biomarkers / Biomarkers - blood / Biomarkers - cerebrospinal fluid / Blood / Blood tests / Brain / Cerebrospinal fluid / cerebrospinal fluid (CSF) / Chitinase-3-Like Protein 1 - blood / Chitinase-3-Like Protein 1 - cerebrospinal fluid / Chitinase-3-Like Protein 1 - genetics / Clinical information / Deoxyribonucleic acid / Disease / DNA / DNA methylation / DNA Methylation - genetics / epigenetics / epigenome‐wide association study (EWAS) / Female / Genetic diversity / Genetics / Genome-Wide Association Study / genome‐wide association study (GWAS) / Genotypes / Humans / Life Sciences / Lipoproteins / Localization / Male / methylation quantitative trait loci (mQTL) / Middle Aged / mild cognitive impairment (MCI) / Network analysis / Neurodegeneration / neurofilament light (NfL) / Neurofilament Proteins - blood / Neurofilament Proteins - cerebrospinal fluid / Pathophysiology / protein quantitative trait loci (pQTL) / tau / Variants / YKL‐40