title: Association between GAB2 haplotype and higher glucose metabolism in Alzheimer's disease-affected brain regions in cognitively normal APOEε4 carriers.
abstract: In a genome-wide association study (GWAS) of late-onset Alzheimer's disease (AD), we found an association between common haplotypes of the GAB2 gene and AD risk in carriers of the apolipoprotein E (APOE) ε4 allele, the major late-onset AD susceptibility gene. We previously proposed the use of fluorodeoxyglucose positron emission tomography (FDG-PET) measurements as a quantitative pre-symptomatic endophenotype, more closely related to disease risk than the clinical syndrome itself, to help evaluate putative genetic and non-genetic modifiers of AD risk. In this study, we examined the relationship between the presence or absence of the relatively protective GAB2 haplotype and PET measurements of regional-to-whole brain FDG uptake in several AD-affected brain regions in 158 cognitively normal late-middle-aged APOEε4 homozygotes, heterozygotes, and non-carriers. GAB2 haplotypes were characterized using Affymetrix Genome-Wide Human SNP 6.0 Array data from each of these subjects. As predicted, the possibly protective GAB2 haplotype was associated with higher regional-to-whole brain FDG uptake in AD-affected brain regions in APOEε4 carriers. While additional studies are needed, this study supports the association between the possibly protective GAB2 haplotype and the risk of late-onset AD in APOEε4 carriers. It also supports the use of brain-imaging endophenotypes to help assess possible modifiers of AD risk.
authors.affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
authors.forename: Winnie S
authors.initials: WS
authors.lastname: Liang
authors.forename: Kewei
authors.initials: K
authors.lastname: Chen
authors.forename: Wendy
authors.initials: W
authors.lastname: Lee
authors.forename: Kunal
authors.initials: K
authors.lastname: Sidhar
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Corneveaux
authors.forename: April N
authors.initials: AN
authors.lastname: Allen
authors.forename: Amanda
authors.initials: A
authors.lastname: Myers
authors.forename: Stephen
authors.initials: S
authors.lastname: Villa
authors.forename: Bessie
authors.initials: B
authors.lastname: Meechoovet
authors.forename: Jeremy
authors.initials: J
authors.lastname: Pruzin
authors.forename: Daniel
authors.initials: D
authors.lastname: Bandy
authors.forename: Adam S
authors.initials: AS
authors.lastname: Fleisher
authors.forename: Jessica B S
authors.initials: JB
authors.lastname: Langbaum
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.forename: Kendall
authors.initials: K
authors.lastname: Jensen
authors.forename: Travis
authors.initials: T
authors.lastname: Dunckley
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Caselli
authors.forename: Susan
authors.initials: S
authors.lastname: Kaib
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism*; D053327:Apolipoprotein E4 / Q000235:genetics*; D001921:Brain / Q000000981:diagnostic imaging; D001923:Brain Chemistry / Q000235:genetics*; D003071:Cognition / Q000502:physiology; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism*; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053327:Apolipoprotein E4; C490895:GAB2 protein, human; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D004247:DNA; D005947:Glucose