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, Andrew J. Sharp, Leonard Schalkwyk, Vahram Haroutunian, Wolfgang Viechtbauer, Daniel L. A. Hove, Michael Weedon, Danielle Brokaw, Paul T. Francis, Alan J. Thomas, Seth Love, Kevin Morgan, Jörn Walter, Paul D. Coleman, David A. Bennett, Philip L. Jager, Jonathan Mill and Katie Lunnon ()
Additional contact information
Rebecca G. Smith: University of Exeter
Ehsan Pishva: University of Exeter
Gemma Shireby: University of Exeter
Adam R. Smith: University of Exeter
Janou A. Y. Roubroeks: University of Exeter
Eilis Hannon: University of Exeter
Gregory Wheildon: University of Exeter
Diego Mastroeni: Arizona State University
Gilles Gasparoni: University of Saarland (UdS)
Matthias Riemenschneider: Saarland University Hospital (UKS)
Armin Giese: Ludwig-Maximilians-University (LMU)
Andrew J. Sharp: Icahn School of Medicine at Mount Sinai
Leonard Schalkwyk: University of Essex
Vahram Haroutunian: The Icahn School of Medicine at Mount Sinai
Wolfgang Viechtbauer: Maastricht University
Daniel L. A. Hove: Maastricht University
Michael Weedon: University of Exeter
Danielle Brokaw: Arizona State University
Paul T. Francis: University of Exeter
Alan J. Thomas: Newcastle University
Seth Love: University of Bristol
Kevin Morgan: University of Nottingham
Jörn Walter: University of Saarland (UdS)
Paul D. Coleman: Arizona State University
David A. Bennett: Rush University Medical Center
Philip L. Jager: Columbia University Medical Center
Jonathan Mill: University of Exeter
Katie Lunnon: University of Exeter

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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/ ).

Date: 2021
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DOI: 10.1038/s41467-021-23243-4

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