Entorhinal cortex epigenome-wide association study highlights four novel loci showing differential methylation in Alzheimer’s disease

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Abstract

Background: Studies on DNA methylation (DNAm) in Alzheimer’s disease (AD) have recently highlighted several genomic loci showing association with disease onset and progression. Methods: Here, we conducted an epigenome-wide association study (EWAS) using DNAm profiles in entorhinal cortex (EC) from 149 AD patients and control brains and combined these with two previously published EC datasets by meta-analysis (total n = 337). Results: We identified 12 cytosine-phosphate-guanine (CpG) sites showing epigenome-wide significant association with either case–control status or Braak’s tau-staging. Four of these CpGs, located in proximity to CNFN/LIPE, TENT5A, PALD1/PRF1, and DIRAS1, represent novel findings. Integrating DNAm levels with RNA sequencing-based mRNA expression data generated in the same individuals showed significant DNAm-mRNA correlations for 6 of the 12 significant CpGs. Lastly, by calculating rates of epigenetic age acceleration using two recently proposed “epigenetic clock” estimators we found a significant association with accelerated epigenetic aging in the brains of AD patients vs. controls. Conclusion: In summary, our study represents the hitherto most comprehensive EWAS in AD using EC and highlights several novel differentially methylated loci with potential effects on gene expression.

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Sommerer, Y., Dobricic, V., Schilling, M., Ohlei, O., Sabet, S. S., Wesse, T., … Bertram, L. (2023). Entorhinal cortex epigenome-wide association study highlights four novel loci showing differential methylation in Alzheimer’s disease. Alzheimer’s Research and Therapy, 15(1). https://doi.org/10.1186/s13195-023-01232-7

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