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

Alzheimers Dement. 2015 Jun;11(6):658-71. doi: 10.1016/j.jalz.2014.05.1757. Epub 2014 Dec 20.

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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism*
  • Brain / metabolism*
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • Polymorphism, Single Nucleotide

Grant support