An epigenetic signature in peripheral blood associated with the haplotype on 17q21.31, a risk factor for neurodegenerative tauopathy.

TitleAn epigenetic signature in peripheral blood associated with the haplotype on 17q21.31, a risk factor for neurodegenerative tauopathy.
Publication TypeJournal Article
Year of Publication2014
AuthorsLi Y, Chen JA, Sears RL, Gao F, Klein ED, Karydas A, Geschwind MD, Rosen HJ, Boxer AL, Guo W, Pellegrini M, Horvath S, Miller BL, Geschwind DH, Coppola G
JournalPLoS Genet
Volume10
Issue3
Paginatione1004211
Date Published2014 Mar
ISSN1553-7404
KeywordsBrain, Chromosomes, Human, Pair 17, DNA Methylation, Epigenesis, Genetic, Frontotemporal Dementia, Genetic Association Studies, Genetic Predisposition to Disease, Haplotypes, Humans, Neurodegenerative Diseases, Risk Factors, Supranuclear Palsy, Progressive, tau Proteins, Tauopathies
Abstract

Little is known about how changes in DNA methylation mediate risk for human diseases including dementia. Analysis of genome-wide methylation patterns in patients with two forms of tau-related dementia--progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD)--revealed significant differentially methylated probes (DMPs) in patients versus unaffected controls. Remarkably, DMPs in PSP were clustered within the 17q21.31 region, previously known to harbor the major genetic risk factor for PSP. We identified and replicated a dose-dependent effect of the risk-associated H1 haplotype on methylation levels within the region in blood and brain. These data reveal that the H1 haplotype increases risk for tauopathy via differential methylation at that locus, indicating a mediating role for methylation in dementia pathophysiology.

DOI10.1371/journal.pgen.1004211
Alternate JournalPLoS Genet.
PubMed ID24603599
PubMed Central IDPMC3945475
Grant ListR01 AG026938 / AG / NIA NIH HHS / United States
T32 GM008042 / GM / NIGMS NIH HHS / United States
R01 AG038791 / AG / NIA NIH HHS / United States
RC1AG035610 / AG / NIA NIH HHS / United States
P30NS062691 / NS / NINDS NIH HHS / United States
P50 AG023501 / AG / NIA NIH HHS / United States
AG031278 / AG / NIA NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
R01 AG032306 / AG / NIA NIH HHS / United States
AG038791 / AG / NIA NIH HHS / United States
F31 NS084556 / NS / NINDS NIH HHS / United States
AG032306 / AG / NIA NIH HHS / United States
AG031189 / AG / NIA NIH HHS / United States