title: Functional screening of Alzheimer pathology genome-wide association signals in Drosophila.
abstract: 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.
authors.affiliation: Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Shulman
authors.forename: Portia
authors.initials: P
authors.lastname: Chipendo
authors.forename: Lori B
authors.initials: LB
authors.lastname: Chibnik
authors.forename: Cristin
authors.initials: C
authors.lastname: Aubin
authors.forename: Dong
authors.initials: D
authors.lastname: Tran
authors.forename: Brendan T
authors.initials: BT
authors.lastname: Keenan
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Kramer
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.forename: Mel B
authors.initials: MB
authors.lastname: Feany
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D004330:Drosophila / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D016678:Genome; D055106:Genome-Wide Association Study; D051272:Glucose Transporter Type 1 / Q000235:genetics; D006801:Humans; D016874:Neurofibrillary Tangles / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci; D015398:Signal Transduction; D016875:tau Proteins / Q000235:genetics
chemical_list: D051272:Glucose Transporter Type 1; D016875:tau Proteins