Alzheimery's disease pathology is associated with early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci

Here, we leverage a unique collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We find that the level of methylation at 71 of the 415,848 interrogated CpGs is significantly associated with th...

Descripción completa

Detalles Bibliográficos
Autores principales: De Jager, PL, Srivastava, G, Lunnon, K, Burgess, J, Schalkwyk, LC, Yu, L, Eaton, ML, Keenan, BT, Ernst, J, McCabe, C, Tang, A, Raj, T, Replogle, J, Brodeur, W, Gabriel, S, Chai, HS, Younkin, C, Younkin, SG, Zou, F, Szyf, M, Epstein, CB, Schneider, JA, Bernstein, BE, Meissner, A, Ertekin-Taner, N, Chibnik, LB, Kellis, M, Mill, J, Bennett, DA
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292795/
https://www.ncbi.nlm.nih.gov/pubmed/25129075
http://dx.doi.org/10.1038/nn.3786
Descripción
Sumario:Here, we leverage a unique collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We find that the level of methylation at 71 of the 415,848 interrogated CpGs is significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validate 11 of the differentially methylated regions in an independent set of 117 subjects. Further, we functionally validate these CpG associations and identify the nearby genes whose RNA expression is altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, RNF34, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD since (1) they are seen in presymptomatic subjects and (2) six of the validated genes connect to a known AD susceptibility gene network.

Ejemplares similares