Association and heterogeneity at the GAPDH locus in Alzheimer's disease

Mariet Allen, Claire Cox, Olivia Belbin, Li Ma, Gina D. Bisceglio, Samantha L. Wilcox, Chanley C. Howell, Talisha A. Hunter, Oliver Culley, Louise P. Walker, Minerva M Carrasquillo, Dennis W Dickson, Ronald Carl Petersen, Neill R Graff Radford, Steven G Younkin, Nilufer Taner

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
JournalNeurobiology of Aging
Volume33
Issue number1
DOIs
StatePublished - Jan 2012

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Glyceraldehyde-3-Phosphate Dehydrogenases
Alzheimer Disease
Single Nucleotide Polymorphism
Meta-Analysis
Alleles
Odds Ratio
Confidence Intervals
Genes
High-Throughput Nucleotide Sequencing
5' Untranslated Regions
Direction compound

Keywords

  • Alzheimer's disease
  • Association studies in genetics
  • Case control studies

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Aging
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Association and heterogeneity at the GAPDH locus in Alzheimer's disease. / Allen, Mariet; Cox, Claire; Belbin, Olivia; Ma, Li; Bisceglio, Gina D.; Wilcox, Samantha L.; Howell, Chanley C.; Hunter, Talisha A.; Culley, Oliver; Walker, Louise P.; Carrasquillo, Minerva M; Dickson, Dennis W; Petersen, Ronald Carl; Graff Radford, Neill R; Younkin, Steven G; Taner, Nilufer.

In: Neurobiology of Aging, Vol. 33, No. 1, 01.2012.

Research output: Contribution to journalArticle

Allen, Mariet ; Cox, Claire ; Belbin, Olivia ; Ma, Li ; Bisceglio, Gina D. ; Wilcox, Samantha L. ; Howell, Chanley C. ; Hunter, Talisha A. ; Culley, Oliver ; Walker, Louise P. ; Carrasquillo, Minerva M ; Dickson, Dennis W ; Petersen, Ronald Carl ; Graff Radford, Neill R ; Younkin, Steven G ; Taner, Nilufer. / Association and heterogeneity at the GAPDH locus in Alzheimer's disease. In: Neurobiology of Aging. 2012 ; Vol. 33, No. 1.
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AU - Allen, Mariet

AU - Cox, Claire

AU - Belbin, Olivia

AU - Ma, Li

AU - Bisceglio, Gina D.

AU - Wilcox, Samantha L.

AU - Howell, Chanley C.

AU - Hunter, Talisha A.

AU - Culley, Oliver

AU - Walker, Louise P.

AU - Carrasquillo, Minerva M

AU - Dickson, Dennis W

AU - Petersen, Ronald Carl

AU - Graff Radford, Neill R

AU - Younkin, Steven G

AU - Taner, Nilufer

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AB - 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.

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