TY - JOUR
T1 - Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD study
AU - Smith, Rebecca G
AU - Pishva, Ehsan
AU - Kouhsar, Morteza
AU - Imm, Jennifer
AU - Dobricic, Valerija
AU - Johannsen, Peter
AU - Wittig, Michael
AU - Franke, Andre
AU - Vandenberghe, Rik
AU - Schaeverbeke, Jolien
AU - Freund-Levi, Yvonne
AU - Frölich, Lutz
AU - Scheltens, Philip
AU - Teunissen, Charlotte E
AU - Frisoni, Giovanni
AU - Blin, Olivier
AU - Richardson, Jill C
AU - Bordet, Régis
AU - Engelborghs, Sebastiaan
AU - de Roeck, Ellen
AU - Martinez-Lage, Pablo
AU - Altuna, Miren
AU - Tainta, Mikel
AU - Lleó, Alberto
AU - Sala, Isabel
AU - Popp, Julius
AU - Peyratout, Gwendoline
AU - Winchester, Laura
AU - Nevado-Holgado, Alejo
AU - Verhey, Frans
AU - Tsolaki, Magda
AU - Andreasson, Ulf
AU - Blennow, Kaj
AU - Zetterberg, Henrik
AU - Streffer, Johannes
AU - Vos, Stephanie J B
AU - Lovestone, Simon
AU - Visser, Pieter Jelle
AU - Bertram, Lars
AU - Lunnon, Katie
N1 - © 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
PY - 2024/10
Y1 - 2024/10
N2 - 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.
AB - 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.
KW - Aged
KW - Alzheimer Disease/genetics
KW - Biomarkers/cerebrospinal fluid
KW - Chitinase-3-Like Protein 1/cerebrospinal fluid
KW - DNA Methylation/genetics
KW - Female
KW - Genome-Wide Association Study
KW - Humans
KW - Male
KW - Middle Aged
KW - Neurofilament Proteins/cerebrospinal fluid
UR - http://www.scopus.com/inward/record.url?scp=85202547146&partnerID=8YFLogxK
U2 - 10.1002/alz.14098
DO - 10.1002/alz.14098
M3 - Journal article
C2 - 39193893
SN - 1552-5260
VL - 20
SP - 6722
EP - 6739
JO - Alzheimer's & dementia : the journal of the Alzheimer's Association
JF - Alzheimer's & dementia : the journal of the Alzheimer's Association
IS - 10
ER -