Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD study.
Smith RG., 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 CE., Frisoni G., Blin O., Richardson JC., Bordet R., 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 SJB., Lovestone S., Visser PJ., Bertram L., Lunnon K.
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.