Association between GAB2 haplotype and higher glucose metabolism in Alzheimer's disease-affected brain regions in cognitively normal APOEε4 carriers.
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.
Liang
Winnie S
WS
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
Chen
Kewei
K
Lee
Wendy
W
Sidhar
Kunal
K
Corneveaux
Jason J
JJ
Allen
April N
AN
Myers
Amanda
A
Villa
Stephen
S
Meechoovet
Bessie
B
Pruzin
Jeremy
J
Bandy
Daniel
D
Fleisher
Adam S
AS
Langbaum
Jessica B S
JB
Huentelman
Matthew J
MJ
Jensen
Kendall
K
Dunckley
Travis
T
Caselli
Richard J
RJ
Kaib
Susan
S
Reiman
Eric M
EM
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
D048868:Adaptor Proteins, Signal Transducing; D053327:Apolipoprotein E4; C490895:GAB2 protein, human; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D004247:DNA; D005947:Glucose