Convergent genetic and expression data implicate immunity in Alzheimer's disease

International Genomics of Alzheimer's Disease Consortium (IGAP)

Research output: Contribution to journalArticle

108 Scopus citations

Abstract

Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10-12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10-11), cholesterol transport (P = 2.96 × 10-9), and proteasome-ubiquitin activity (P = 1.34 × 10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P =.002-.05). Conclusions: The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.

Original languageEnglish (US)
Pages (from-to)658-671
Number of pages14
JournalAlzheimer's and Dementia
Volume11
Issue number6
DOIs
StatePublished - Jun 1 2015

Keywords

  • ALIGATOR
  • Alzheimer's disease
  • Cholesterol metabolism
  • Dementia
  • Endocytosis
  • Immune response
  • Neurodegeneration
  • Pathway analysis
  • Ubiquitination
  • Weighted gene co-expression network analysis

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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