A meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex

Rebecca G Smith, Ehsan Pishva, Gemma Shireby, Adam R Smith, Janou A Y Roubroeks, Eilis Hannon, Gregory Wheildon, Diego Mastroeni, Gilles Gasparoni, Matthias Riemenschneider, Armin Giese, Leonard Schalkwyk, Vahram Haroutunian, Wolfgang Viechtbauer, Daniel L A van den Hove, Michael Weedon, Danielle Brokaw, Paul T Francis, Seth Love, Kevin MorganJörn Walter, Paul D Coleman, Philip L De Jager, Jonathan Mill, Katie Lunnon*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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 = 1453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 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 = 1408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further >600 unique donors. The meta-analysis summary statistics are available in our online data resource (www.epigenomicslab.com/ad-meta-analysis/).

Original languageEnglish
Article number3517 (2021)
Number of pages13
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 10 Jun 2021

Bibliographical note

Funding Information:
This work was funded by a major project grant from the Alzheimer’s Society UK (AS-PG-14-038) to K.L., an Alzheimer’s Association US New Investigator Research Grant (NIRG-14-320878) to K.L. and a project grant from the Medical Research Council (MRC) (MR/N027973/1) to K.L. as part of a larger collaborative project funded to K.L. and D.L.A.v.d.H. for the EPI-AD consortium through the Joint Programme—Neurodegenerative Disease Research (JPND) initiative. This work was also supported through a ZonMw Memorabel Grant (733050516) to E.P. Data analysis was undertaken using high-performance computing supported by a Medical Research Council (MRC) Clinical Infrastructure Award (M008924) to J.M. The project was also supported through PhD studentships from the Alzheimer’s Society (G.S.), BRACE (Bristol Research into Alzheimer’s and Care of the Elderly) (G.W.) and the MRC GW4 Doctoral Training Program (DTP) (J.A.Y.R.). BDR is jointly funded by Alzheimer’s Research UK and the Alzheimer’s Society in association with the MRC. DNA methylation data generated in the Brains for Dementia Research cohort was supported by the Alzheimer’s Society and Alzheimer’s Research UK (ARUK). Research reported in this publication was also supported by the National Institute of Aging of the National Institutes of Health under award numbers P30AG19610, P30AG10161, R01AG15819, R01AG17917, R01AG36042, R01AG036039, R01AG036400 and R01AG067015. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank the donors and families who have made this research possible.

Publisher Copyright:
© 2021, The Author(s).

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