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

Yun Li; Jason A Chen; Renee L Sears; Fuying Gao; Eric D Klein; Anna Karydas; Michael D Geschwind; Howard J Rosen; Adam L Boxer; Weilong Guo; Matteo Pellegrini; Steve Horvath; Bruce L Miller; Daniel H Geschwind; Giovanni Coppola

doi:10.1371/journal.pgen.1004211

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

PLoS Genet. 2014 Mar 6;10(3):e1004211. doi: 10.1371/journal.pgen.1004211. eCollection 2014 Mar.

Authors

Affiliations

¹ Department of Psychiatry and Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
² Interdepartmental Program in Bioinformatics, University of California Los Angeles, Los Angeles, California, United States of America.
³ Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
⁴ Memory and Aging Center/Sandler Neurosciences Center, University of California San Francisco, San Francisco, California, United States of America.
⁵ Bioinformatics Division and Center for Synthetic & Systems Biology, TNLIST, Tsinghua University, Beijing, China; Department of Molecular, Cell and Developmental Biology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
⁶ Department of Molecular, Cell and Developmental Biology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
⁷ Departments of Biostatistics and Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
⁸ Department of Psychiatry and Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Brain / metabolism
Brain / pathology
Chromosomes, Human, Pair 17
DNA Methylation / genetics*
Epigenesis, Genetic*
Frontotemporal Dementia / genetics*
Frontotemporal Dementia / pathology
Genetic Association Studies
Genetic Predisposition to Disease
Haplotypes
Humans
Neurodegenerative Diseases
Risk Factors
Supranuclear Palsy, Progressive / genetics*
Supranuclear Palsy, Progressive / pathology
Tauopathies / etiology
Tauopathies / genetics*
Tauopathies / pathology
tau Proteins / genetics

Substances

MAPT protein, human
tau Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding