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

dc.contributor.authorSmith, R. G.
dc.contributor.authorPishva, E.
dc.contributor.authorShireby, G.
dc.contributor.authorSmith, A. R.
dc.contributor.authorRoubroeks, J. A. Y.
dc.contributor.authorHannon, E.
dc.contributor.authorWheildon, G.
dc.contributor.authorMastroeni, D.
dc.contributor.authorGasparoni, G.
dc.contributor.authorRiemenschneider, M.
dc.contributor.authorGiese, A.
dc.contributor.authorSharp, A. J.
dc.contributor.authorSchalkwyk, L.
dc.contributor.authorHaroutunian, V.
dc.contributor.authorViechtbauer, W.
dc.contributor.authorvan den Hove, D. L. A.
dc.contributor.authorWeedon, M.
dc.contributor.authorBrokaw, D.
dc.contributor.authorFrancis, P. T.
dc.contributor.authorThomas, A. J.
dc.contributor.authorLove, S.
dc.contributor.authorMorgan, K.
dc.contributor.authorWalter, J.
dc.contributor.authorColeman, P. D.
dc.contributor.authorBennett, D. A.
dc.contributor.authorDe Jager, P. L.
dc.contributor.authorMill, J.
dc.contributor.authorLunnon, K.
dc.description.abstractEpigenome-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/ ).
dc.description.admin-notePublished version, accepted version
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dc.identifier.citationSmith, R. G., Pishva, E., Shireby, G., Smith, A. R., Roubroeks, J. A. Y., Hannon, E., Wheildon, G., Mastroeni, D., Gasparoni, G., Riemenschneider, M., Giese, A., 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., Love, S., Morgan, K., Walter, J., Coleman, P. D., Bennett, D. A., De Jager, P. L., Mill, J. and Lunnon, K. (2021) 'A meta-analysis of epigenome-wide association studies in Alzheimer's disease highlights novel differentially methylated loci across cortex', Nature Communications, 12(1), pp. 3517.
dc.identifier.journalNature Communications
dc.rights© The Author(s) 2021 Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License.
dc.subjectAged, 80 and over
dc.subjectAlzheimer Disease/*genetics/*metabolism/pathology
dc.subjectCohort Studies
dc.subjectCpG Islands
dc.subject*DNA Methylation
dc.subjectEntorhinal Cortex/*metabolism/pathology
dc.subjectEpigenesis, Genetic
dc.subjectGenome-Wide Association Study
dc.subjectMiddle Aged
dc.subjectPrefrontal Cortex/*metabolism/pathology
dc.subjectROC Curve
dc.subjectTemporal Lobe/*metabolism/pathology
dc.titleA meta-analysis of epigenome-wide association studies in Alzheimer's disease highlights novel differentially methylated loci across cortex
dc.type.versionPublished online