Functional screening of Alzheimer pathology genome-wide association signals in Drosophila

Am J Hum Genet. 2011 Feb 11;88(2):232-8. doi: 10.1016/j.ajhg.2011.01.006. Epub 2011 Feb 3.


We have leveraged a Drosophila model relevant to Alzheimer disease (AD) for functional screening of findings from a genome-wide scan for loci associated with a quantitative measure of AD pathology in humans. In six of the 15 genomic regions evaluated, we successfully identified a causal gene for the association, on the basis of in vivo interactions with the neurotoxicity of Tau, which forms neurofibrillary tangles in AD. Among the top results, rs10845990 within SLC2A14, encoding a glucose transporter, showed evidence of replication for association with AD pathology, and gain and loss of function in glut1, the Drosophila ortholog, was associated with suppression and enhancement of Tau toxicity, respectively. Our strategy of coupling genome-wide association in humans with functional screening in a model organism is likely to be a powerful approach for gene discovery in AD and other complex genetic disorders.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology*
  • Animals
  • Drosophila / genetics*
  • Genetic Predisposition to Disease
  • Genome*
  • Genome-Wide Association Study
  • Glucose Transporter Type 1 / genetics
  • Humans
  • Neurofibrillary Tangles / genetics*
  • Neurofibrillary Tangles / pathology*
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics*
  • Quantitative Trait Loci
  • Signal Transduction
  • tau Proteins / genetics


  • Glucose Transporter Type 1
  • tau Proteins