title: Alzheimer's loci: epigenetic associations and interaction with genetic factors.
abstract: OBJECTIVE
  We explore the role of DNA methylation in Alzheimer's disease (AD). To elucidate where DNA methylation falls along the causal pathway linking risk factors to disease, we examine causal models to assess its role in the pathology of AD.
  
  
  METHODS
  DNA methylation profiles were generated in 740 brain samples using the Illumina HumanMet450K beadset. We focused our analysis on CpG sites from 11 AD susceptibility gene regions. The primary outcome was a quantitative measure of neuritic amyloid plaque (NP), a key early element of AD pathology. We tested four causal models: (1) independent associations, (2) CpG mediating the association of a variant, (3) reverse causality, and (4) genetic variant by CpG interaction.
  
  
  RESULTS
  Six genes regions (17 CpGs) showed evidence of CpG associations with NP, independent of genetic variation - BIN1 (5), CLU (5), MS4A6A (3), ABCA7 (2), CD2AP (1), and APOE (1). Together they explained 16.8% of the variability in NP. An interaction effect was seen in the CR1 region for two CpGs, cg10021878 (P = 0.01) and cg05922028 (P = 0.001), in relation to NP. In both cases, subjects with the risk allele rs6656401(AT) (/) (AA) display more methylation being associated with more NP burden, whereas subjects with the rs6656401(TT) protective genotype have an inverse association with more methylation being associated with less NP.
  
  
  CONCLUSIONS
  These observations suggest that, within known AD susceptibility loci, methylation is related to pathologic processes of AD and may play a largely independent role by influencing gene expression in AD susceptibility loci.
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital Boston, Massachusetts, 02115 ; Department of Neurology, Harvard Medical School Boston, Massachusetts, 02115 ; Medical and Population Genetics, Broad Institute of MIT and Harvard Cambridge, Massachusetts, 02142 ; Department of Epidemiology, Harvard T.H. Chan School of Public Health Boston, Massachusetts, 02115.
authors.forename: Lori B
authors.initials: LB
authors.lastname: Chibnik
authors.affiliation: Medical and Population Genetics, Broad Institute of MIT and Harvard Cambridge, Massachusetts, 02142 ; Rush Alzheimer's Disease Center, Rush University Medical Center Chicago, Illinois, 60612.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: Medical and Population Genetics, Broad Institute of MIT and Harvard Cambridge, Massachusetts, 02142 ; Computer Science and Artificial Intelligence Laboratory, MIT Cambridge, Massachusetts, 02124.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Eaton
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital Boston, Massachusetts, 02115 ; Department of Neurology, Harvard Medical School Boston, Massachusetts, 02115 ; Medical and Population Genetics, Broad Institute of MIT and Harvard Cambridge, Massachusetts, 02142.
authors.forename: Gyan
authors.initials: G
authors.lastname: Srivastava
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center Chicago, Illinois, 60612.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.affiliation: Medical and Population Genetics, Broad Institute of MIT and Harvard Cambridge, Massachusetts, 02142 ; Computer Science and Artificial Intelligence Laboratory, MIT Cambridge, Massachusetts, 02124.
authors.forename: Manolis
authors.initials: M
authors.lastname: Kellis
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center Chicago, Illinois, 60612.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital Boston, Massachusetts, 02115 ; Department of Neurology, Harvard Medical School Boston, Massachusetts, 02115 ; Medical and Population Genetics, Broad Institute of MIT and Harvard Cambridge, Massachusetts, 02142.
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager