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 L. Shireby; Adam R. Smith; Janou A. Y. Roubroeks; Eilis J. Hannon; Greg Wheildon; Diego Mastroeni; Gilles Gasparoni; Markus J. Riemenschneider; Armin Giese; Andrew J. Sharp; Leonard C. Schalkwyk; Vahram H. Haroutunian; Wolfgang Viechtbauer; Daniël van den Hove; Michael N. Weedon; Danielle L. Brokaw; Paul T. Francis; Alan J. Thomas; Seth Love; Kevin Morgan; Jörn Walter; Paul D. Coleman; David Alan Bennett; Philip L. De Jager; Jonathan S. Mill; Katie Lunnon

doi:10.1038/s41467-021-23243-4

GenomicsNature CommunicationsJun 10, 2021

Peer-reviewed journal article

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

Rebecca G. Smith iD, Ehsan Pishva iD, Gemma L. Shireby iD, Adam R. Smith iD, Janou A. Y. Roubroeks iD, Eilis J. Hannon iD, Greg Wheildon iD, Diego Mastroeni iD, Gilles Gasparoni iD, Markus J. Riemenschneider iD, Armin Giese iD, Andrew J. Sharp iD, Leonard C. Schalkwyk iD, Vahram H. Haroutunian iD, Wolfgang Viechtbauer iD, Daniël van den Hove iD, Michael N. Weedon iD, Danielle L. Brokaw, Paul T. Francis iD, Alan J. Thomas iD, Seth Love iD, Kevin Morgan iD, Jörn Walter iD, Paul D. Coleman iD, David Alan Bennett iD, , Katie Lunnon iD

Abstract

Epigenome-wide association studies of Alzheimers 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 Alzheimers disease (N=1,453 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=1,408 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/).

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