title: Association of Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 with pathological diagnosis of Alzheimer disease.
abstract: OBJECTIVE
  Recent large-scale genome-wide association studies have discovered several genetic variants associated with Alzheimer disease (AD); however, the extent to which DNA methylation in these AD loci contributes to the disease susceptibility remains unknown.
  
  
  OBJECTIVE
  To examine the association of brain DNA methylation in 28 reported AD loci with AD pathologies.
  
  
  METHODS
  Ongoing community-based clinical pathological cohort studies of aging and dementia (the Religious Orders Study and the Rush Memory and Aging Project) among 740 autopsied participants 66.0 to 108.3 years old.
  
  
  METHODS
  DNA methylation levels at individual CpG sites generated from dorsolateral prefrontal cortex tissue using a bead assay.
  
  
  METHODS
  Pathological diagnosis of AD by National Institute on Aging-Reagan criteria following a standard postmortem examination.
  
  
  RESULTS
  Overall, 447 participants (60.4%) met the criteria for pathological diagnosis of AD. Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 was associated with pathological AD. The association was robustly retained after replacing the binary trait of pathological AD with 2 quantitative and molecular specific hallmarks of AD, namely, Aβ load and paired helical filament tau tangle density. Furthermore, RNA expression of transcripts of SORL1 and ABCA7 was associated with paired helical filament tau tangle density, and the expression of BIN1 was associated with Aβ load.
  
  
  CONCLUSIONS
  Brain DNA methylation in multiple AD loci is associated with AD pathologies. The results provide further evidence that disruption of DNA methylation is involved in the pathological process of AD.
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois2Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts4Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departme.
authors.forename: Lori B
authors.initials: LB
authors.lastname: Chibnik
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts4Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departme.
authors.forename: Gyan P
authors.initials: GP
authors.lastname: Srivastava
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts4Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departme.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pochet
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois2Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.
authors.forename: Jingyun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts4Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departme.
authors.forename: Jishu
authors.initials: J
authors.lastname: Xu
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts4Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departme.
authors.forename: James
authors.initials: J
authors.lastname: Kozubek
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts4Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departme.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Obholzer
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois2Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois7Department of Preventive Medicine, Rush University Medical Center, Chicago, Illinois.
authors.forename: Sue E
authors.initials: SE
authors.lastname: Leurgans
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois2Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois8Department of Pathology, Rush University Medical Center, Chicago, Illinois.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.affiliation: Epigenomics Program, Broad Institute, Cambridge Center, Cambridge, Massachusetts10Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts.
authors.forename: Alexander
authors.initials: A
authors.lastname: Meissner
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts4Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departme.
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois2Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D017920:Antiporters / Q000235:genetics*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D059847:HLA-DRB5 Chains / Q000235:genetics*; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D012111:Residence Characteristics; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C411895:ABCA7 protein, human; D018528:ATP-Binding Cassette Transporters; D048868:Adaptor Proteins, Signal Transducing; D017920:Antiporters; C101410:BIN1 protein, human; D059847:HLA-DRB5 Chains; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D009687:Nuclear Proteins; C470570:SLC24A4 protein, human; C102582:SORL1 protein, human; D025521:Tumor Suppressor Proteins