title: Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci.
abstract: We used a 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 found that the level of methylation at 71 of the 415,848 interrogated CpGs was significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validated 11 of the differentially methylated regions in an independent set of 117 subjects. Furthermore, we functionally validated these CpG associations and identified the nearby genes whose RNA expression was altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD given that we observed them in presymptomatic subjects and that six of the validated genes connect to a known AD susceptibility gene network.
authors.affiliation: 1] Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: 1] Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Gyan
authors.initials: G
authors.lastname: Srivastava
authors.affiliation: 1] University of Exeter Medical School, University of Exeter, Exeter, UK. [2] Institute of Psychiatry, King's College London, London, UK.
authors.forename: Katie
authors.initials: K
authors.lastname: Lunnon
authors.affiliation: 1] Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA. [2] Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Burgess
authors.affiliation: 1] University of Exeter Medical School, University of Exeter, Exeter, UK. [2] Institute of Psychiatry, King's College London, London, UK.
authors.forename: Leonard C
authors.identifier: 0000000170305756
authors.initials: LC
authors.lastname: Schalkwyk
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: 1] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. [2] Computer Science and Artificial Intelligence Laboratory (CSAIL), Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Eaton
authors.affiliation: 1] Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Brendan T
authors.initials: BT
authors.lastname: Keenan
authors.affiliation: 1] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. [2] Computer Science and Artificial Intelligence Laboratory (CSAIL), Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Ernst
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Cristin
authors.initials: C
authors.lastname: McCabe
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Tang
authors.affiliation: 1] Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Towfique
authors.initials: T
authors.lastname: Raj
authors.affiliation: 1] Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Replogle
authors.affiliation: Genetic Analysis Platform, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Brodeur
authors.affiliation: Genetic Analysis Platform, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.affiliation: 1] Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA. [2] Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: High S
authors.initials: HS
authors.lastname: Chai
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Curtis
authors.initials: C
authors.lastname: Younkin
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Fanggeng
authors.initials: F
authors.lastname: Zou
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Québec, Canada.
authors.forename: Moshe
authors.initials: M
authors.lastname: Szyf
authors.affiliation: Epigenomics Program, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Epstein
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts, USA. [2] Epigenomics Program, Broad Institute, Cambridge, Massachusetts, USA. [3] Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Bernstein
authors.affiliation: 1] Computer Science and Artificial Intelligence Laboratory (CSAIL), Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [2] Epigenomics Program, Broad Institute, Cambridge, Massachusetts, USA. [3] Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Meissner
authors.affiliation: 1] Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA. [2] Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Nilufer
authors.initials: N
authors.lastname: Ertekin-Taner
authors.affiliation: 1] Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Lori B
authors.initials: LB
authors.lastname: Chibnik
authors.affiliation: 1] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. [2] Computer Science and Artificial Intelligence Laboratory (CSAIL), Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Manolis
authors.initials: M
authors.lastname: Kellis
authors.affiliation: 1] University of Exeter Medical School, University of Exeter, Exeter, UK. [2] Institute of Psychiatry, King's College London, London, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D000686:Amyloidosis / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D017487:Ankyrins / Q000235:genetics*; D001921:Brain / Q000473:pathology / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D060066:Protein Interaction Maps; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C110202:ANK1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D017487:Ankyrins; C101410:BIN1 protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C580845:RHBDF2 protein, human; D025521:Tumor Suppressor Proteins