Association and heterogeneity at the GAPDH locus in Alzheimer's disease.
Glyceraldehyde-3-phosphate dehydrogenase gene (GAPDH) and its paralogs were implicated in late-onset Alzheimer's disease (LOAD), although the strength and direction of association have not been consistent. We genotyped 3 previously reported single nucleotide polymorphisms (SNPs; rs3741916-GAPDH 5' UTR, rs2029721-pGAPD, and rs4806173-GAPDHS) in 3 case-control series (2112 cases and 3808 controls). Rs3741916 showed the strongest LOAD association (p = 0.003). The minor allele of rs3741916 showed a protective effect in our combined series (odds ratio [OR] = 0.87%, 95% confidence interval [CI] = 0.79-0.96). This is consistent with results from the 2 published follow-up studies and in opposite direction of the original report. Meta-analysis of the published series with ours suggests presence of heterogeneity (Breslow-Day p < 0.0001). Meta-analysis of only the follow-up series including ours revealed a significant protective effect for the minor allele of rs3741916 (OR = 0.85%, 95% CI = 0.76-0.96, p = 0.009). Our results support the presence of LOAD variants and heterogeneity at the GAPDH locus. The most promising rs3741916 variant is unlikely to be functional given opposing effects in different series. Identification of functional variant(s) in this region likely awaits deep sequencing.
Allen
Mariet
M
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
Cox
Claire
C
Belbin
Olivia
O
Ma
Li
L
Bisceglio
Gina D
GD
Wilcox
Samantha L
SL
Howell
Chanley C
CC
Hunter
Talisha A
TA
Culley
Oliver
O
Walker
Louise P
LP
Carrasquillo
Minerva M
MM
Dickson
Dennis W
DW
Petersen
Ronald C
RC
Graff-Radford
Neill R
NR
Younkin
Steven G
SG
Ertekin-Taner
Nilüfer
N
D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
D005987:Glyceraldehyde-3-Phosphate Dehydrogenases