title: Genome-wide DNA methylation profiling in the superior temporal gyrus reveals epigenetic signatures associated with Alzheimer's disease.
abstract: BACKGROUND
  Alzheimer's disease affects ~13% of people in the United States 65 years and older, making it the most common neurodegenerative disorder. Recent work has identified roles for environmental, genetic, and epigenetic factors in Alzheimer's disease risk.
  
  
  METHODS
  We performed a genome-wide screen of DNA methylation using the Illumina Infinium HumanMethylation450 platform on bulk tissue samples from the superior temporal gyrus of patients with Alzheimer's disease and non-demented controls. We paired a sliding window approach with multivariate linear regression to characterize Alzheimer's disease-associated differentially methylated regions (DMRs).
  
  
  RESULTS
  We identified 479 DMRs exhibiting a strong bias for hypermethylated changes, a subset of which were independently associated with aging. DMR intervals overlapped 475 RefSeq genes enriched for gene ontology categories with relevant roles in neuron function and development, as well as cellular metabolism, and included genes reported in Alzheimer's disease genome-wide and epigenome-wide association studies. DMRs were enriched for brain-specific histone signatures and for binding motifs of transcription factors with roles in the brain and Alzheimer's disease pathology. Notably, hypermethylated DMRs preferentially overlapped poised promoter regions, marked by H3K27me3 and H3K4me3, previously shown to co-localize with aging-associated hypermethylation. Finally, the integration of DMR-associated single nucleotide polymorphisms with Alzheimer's disease genome-wide association study risk loci and brain expression quantitative trait loci highlights multiple potential DMRs of interest for further functional analysis.
  
  
  CONCLUSIONS
  We have characterized changes in DNA methylation in the superior temporal gyrus of patients with Alzheimer's disease, highlighting novel loci that facilitate better characterization of pathways and mechanisms underlying Alzheimer's disease pathogenesis, and improve our understanding of epigenetic signatures that may contribute to the development of disease.
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Corey T
authors.initials: CT
authors.lastname: Watson
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Mental Illness Research, Education, and Clinical Center (VISN 3), James J. Peters VA Medical Center, Bronx, NY, USA.
authors.forename: Panos
authors.initials: P
authors.lastname: Roussos
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Paras
authors.initials: P
authors.lastname: Garg
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Ho
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Nidha
authors.initials: N
authors.lastname: Azam
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Pavel L
authors.initials: PL
authors.lastname: Katsel
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Mental Illness Research, Education, and Clinical Center (VISN 3), James J. Peters VA Medical Center, Bronx, NY, USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. andrew.sharp@mssm.edu.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sharp
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D013702:Temporal Lobe / Q000378:metabolism