Integrated whole transcriptome and DNA methylation analysis identifies gene networks specific to late-onset Alzheimer's disease

Crystal E. Humphries, Martin A. Kohli, Lubov Nathanson, Patrice Whitehead, Gary Beecham, Eden Martin, Deborah C. Mash, Margaret A. Pericak-Vance, John Gilbert

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Previous transcriptome studies observed disrupted cellular processes in late-onset Alzheimer's disease (LOAD), yet it is unclear whether these changes are specific to LOAD, or are common to general neurodegeneration. In this study, we address this question by examining transcription in LOAD and comparing it to cognitively normal controls and a cohort of 'disease controls.' Differential transcription was examined using RNA-seq, which allows for the examination of protein coding genes, non-coding RNAs, and splicing. Significant transcription differences specific to LOAD were observed in five genes: C10orf105, DIO2, a lincRNA, RARRES3, and WIF1. These findings were replicated in two independent publicly available microarray data sets. Network analyses, performed on 2,504 genes with moderate transcription differences in LOAD, reveal that these genes aggregate into seven networks. Two networks involved in myelination and innate immune response specifically correlated to LOAD. FRMD4B and ST18, hub genes within the myelination network, were previously implicated in LOAD. Of the five significant genes, WIF1 and RARRES3 are directly implicated in the myelination process; the other three genes are located within the network. LOAD specific changes in DNA methylation were located throughout the genome and substantial changes in methylation were identified within the myelination network. Splicing differences specific to LOAD were observed across the genome and were decreased in all seven networks. DNA methylation had reduced influence on transcription within LOAD in the myelination network when compared to both controls. These results hint at the molecular underpinnings of LOAD and indicate several key processes, genes, and networks specific to the disease.

Original languageEnglish (US)
Pages (from-to)977-987
Number of pages11
JournalJournal of Alzheimer's Disease
Issue number3
StatePublished - 2015


  • Alzheimer's disease
  • dementia with Lewy bodies
  • DNA methylation
  • expression
  • human brain
  • Illumina Human Methylation 450K
  • late-onset transcriptome
  • myelination
  • networks
  • RNA-seq
  • splicing

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology


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