Meta-analysis of epigenome-wide association studies in Alzheimer's disease highlights novel differentially methylated loci across cortex

Shireby, Gemma; Smith, Rebecca G; Pishva, Ehsan; Smith, Adam R; Roubroeks, Janou A Y; Hannon, Eilis; Wheildon, Gregory; Mastroeni, Diego; Gasparoni, Gilles; Giese, Armin; Riemenschneider, Matthias; Sharp, Andrew J; Schalkwyk, Leonard; Haroutunian, Vahram; Viechtbauer, Wolfgang; Van Den Hove, Daniel L A; Weedon, Michael; Brokaw, Danielle; Francis, Paul T; Thomas, Alan J; Love, Seth; Morgan, Kevin; Walter, Jörn; Coleman, Paul D; Bennett, David A; De Jager, Philip L; Mill, Jonathan; Lunnon, Katie

Abstract

Epigenome-wide association studies of Alzheimer’s disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer’s disease (N=1,453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identified 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N=1,408 donors) identified 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes had not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a > 600 further unique donors. The meta-analysis summary statistics are available in our online data resource (www.epigenomicslab.com/ad-meta-analysis/).

Citation

Shireby, G., Smith, R. G., Pishva, E., Smith, A. R., Roubroeks, J. A. Y., Hannon, E., Wheildon, G., Mastroeni, D., Gasparoni, G., Giese, A., Riemenschneider, M., Sharp, A. J., Schalkwyk, L., Haroutunian, V., Viechtbauer, W., Van Den Hove, D. L. A., Weedon, M., Brokaw, D., Francis, P. T., Thomas, A. J., …Lunnon, K. (2021). Meta-analysis of epigenome-wide association studies in Alzheimer's disease highlights novel differentially methylated loci across cortex. Nature Communications, 12, Article 3517. https://doi.org/10.1038/s41467-021-23243-4

• Journal Article Type: Article
• Acceptance Date: Apr 16, 2021
• Online Publication Date: Jun 10, 2021
• Publication Date: Jun 10, 2021
• Deposit Date: Apr 21, 2021
• Publicly Available Date: Jun 10, 2021
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Article Number: 3517
• DOI: https://doi.org/10.1038/s41467-021-23243-4
• Public URL: https://nottingham-repository.worktribe.com/output/5486293
• Publisher URL: https://www.nature.com/articles/s41467-021-23243-4