title: Association and heterogeneity at the GAPDH locus in Alzheimer's disease.
abstract: 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.
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
authors.forename: Mariet
authors.initials: M
authors.lastname: Allen
authors.forename: Claire
authors.initials: C
authors.lastname: Cox
authors.forename: Olivia
authors.initials: O
authors.lastname: Belbin
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Gina D
authors.initials: GD
authors.lastname: Bisceglio
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Wilcox
authors.forename: Chanley C
authors.initials: CC
authors.lastname: Howell
authors.forename: Talisha A
authors.initials: TA
authors.lastname: Hunter
authors.forename: Oliver
authors.initials: O
authors.lastname: Culley
authors.forename: Louise P
authors.initials: LP
authors.lastname: Walker
authors.forename: Minerva M
authors.initials: MM
authors.lastname: Carrasquillo
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
authors.forename: Nilüfer
authors.initials: N
authors.lastname: Ertekin-Taner
mesh_terms: 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
chemical_list: D005987:Glyceraldehyde-3-Phosphate Dehydrogenases