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/).
Highlights
Epigenome-wide association studies of Alzheimer’s disease have highlighted neuropathologyassociated DNA methylation differences, existing studies have been limited in sample size and utilized different brain regions
Our data can be explored as part of an online searchable database, which can be found on our website
Far fewer loci were identified in the entorhinal cortex compared to the other cortical regions, this is likely due to the reduced sample size in this tissue
Summary
Epigenome-wide association studies of Alzheimer’s disease have highlighted neuropathologyassociated DNA methylation differences, existing studies have been limited in sample size and utilized different brain regions. In recent years a number of epigenome-wide association studies (EWAS) have been performed in AD brain samples, which have predominantly utilized the Illumina Infinium HumanMethylation450K BeadChip (450K array) in conjunction with bisulfite-treated DNA to assess levels of DNA methylation in cortical brain tissue from donors with varying degrees of AD pathology[5,6,7,8,9,10,11,12] These studies have identified a number of loci that show robust differential DNA methylation in disease, and many of these overlap between studies, for example, loci annotated to ANK1, RHBDF2, HOXA3, CDH23 and RPL13 have been consistently reported. Our meta-analysis approach provides additional power to detect DNA methylomic variation associated with AD pathology at novel loci, in addition to providing further replication of loci that have been previously identified in the smaller independent EWAS
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