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

• Published in: Nature communications Vol. 12; no. 1; p. 3517
• Main Authors: Smith, Rebecca G., Pishva, Ehsan, Shireby, Gemma, Smith, Adam R., Roubroeks, Janou A. Y., Hannon, Eilis, Wheildon, Gregory, Mastroeni, Diego, Gasparoni, Gilles, Riemenschneider, Matthias, Giese, Armin, Sharp, Andrew J., Schalkwyk, Leonard, Haroutunian, Vahram, Viechtbauer, Wolfgang, van den Hove, Daniel L. A., Weedon, Michael, Brokaw, Danielle, Francis, Paul T., Thomas, Alan J., Love, Seth, Morgan, Kevin, Walter, Jörn, Coleman, Paul D., Bennett, David A., De Jager, Philip L., Mill, Jonathan, Lunnon, Katie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.06.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 45/43; 45/61; 631/208/176; 631/208/177; 631/208/212/2142; 631/378/1689/1283; 631/378/2584; Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Brain; Cerebellum; Cohort Studies; Cortex (entorhinal); Cortex (temporal); CpG Islands; Deoxyribonucleic acid; DNA; DNA Methylation; Entorhinal Cortex - metabolism; Entorhinal Cortex - pathology; Epigenesis, Genetic; Epigenome; Female; Genes; Genome-Wide Association Study; Humanities and Social Sciences; Humans; Loci; Male; Meta-analysis; Middle Aged; multidisciplinary; Neurodegenerative diseases; Neuropathology; Prefrontal cortex; Prefrontal Cortex - metabolism; Prefrontal Cortex - pathology; ROC Curve; Science; Science (multidisciplinary); Statistical analysis; Temporal gyrus; Temporal Lobe - metabolism; Temporal Lobe - pathology; Uniqueness
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23243-4

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/ ). Although epigenome-wide association studies of Alzheimer’s disease have highlighted neuropathology-associated DNA methylation differences, previous studies have been limited in sample size and brain region used. Here, the authors combine data from six DNA methylomic studies of Alzheimer’s disease ( N  = 1453 unique individuals) to identify differentially methylated loci across cortex.