title: An epigenetic signature in peripheral blood associated with the haplotype on 17q21.31, a risk factor for neurodegenerative tauopathy.
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.
authors.affiliation: 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.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Interdepartmental Program in Bioinformatics, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Chen
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Renee L
authors.initials: RL
authors.lastname: Sears
authors.affiliation: 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.
authors.forename: Fuying
authors.initials: F
authors.lastname: Gao
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Klein
authors.affiliation: Memory and Aging Center/Sandler Neurosciences Center, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Anna
authors.initials: A
authors.lastname: Karydas
authors.affiliation: Memory and Aging Center/Sandler Neurosciences Center, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Geschwind
authors.affiliation: Memory and Aging Center/Sandler Neurosciences Center, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Rosen
authors.affiliation: Memory and Aging Center/Sandler Neurosciences Center, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Boxer
authors.affiliation: 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.
authors.forename: Weilong
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Molecular, Cell and Developmental Biology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: Departments of Biostatistics and Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
authors.affiliation: Memory and Aging Center/Sandler Neurosciences Center, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: 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.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.affiliation: 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.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
mesh_terms: D001921:Brain / Q000378:metabolism / Q000473:pathology; D002886:Chromosomes, Human, Pair 17; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D019636:Neurodegenerative Diseases; D012307:Risk Factors; D013494:Supranuclear Palsy, Progressive / Q000235:genetics* / Q000473:pathology; D024801:Tauopathies / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D016875:tau Proteins / Q000235:genetics
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins