Linking Protective GAB2 Variants, Increased Cortical GAB2 Expression and Decreased Alzheimer's Disease Pathology

Fanggeng Zou, Olivia Belbin, Minerva M Carrasquillo, Oliver J. Culley, Talisha A. Hunter, Li Ma, Gina D. Bisceglio, Mariet Allen, Dennis W Dickson, Neill R Graff Radford, Ronald Carl Petersen, Kevin Morgan, Steven G Younkin

Research output: Contribution to journalArticle

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Abstract

GRB-associated binding protein 2 (GAB2) represents a compelling genome-wide association signal for late-onset Alzheimer's disease (LOAD) with reported odds ratios (ORs) ranging from 0.75-0.85. We tested eight GAB2 variants in four North American Caucasian case-control series (2,316 LOAD, 2,538 controls) for association with LOAD. Meta-analyses revealed ORs ranging from (0.61-1.20) with no significant association (all p>0.32). Four variants were hetergeneous across the populations (all p<0.02) due to a potentially inflated effect size (OR = 0.61-0.66) only observed in the smallest series (702 LOAD, 209 controls). Despite the lack of association in our series, the previously reported protective association for GAB2 remained after meta-analyses of our data with all available previously published series (11,952-22,253 samples; OR = 0.82-0.88; all p<0.04). Using a freely available database of lymphoblastoid cell lines we found that protective GAB2 variants were associated with increased GAB2 expression (p = 9.5×10-7-9.3×10-6). We next measured GAB2 mRNA levels in 249 brains and found that decreased neurofibrillary tangle (r = -0.34, p = 0.0006) and senile plaque counts (r = -0.32, p = 0.001) were both good predictors of increased GAB2 mRNA levels albeit that sex (r = -0.28, p = 0.005) may have been a contributing factor. In summary, we hypothesise that GAB2 variants that are protective against LOAD in some populations may act functionally to increase GAB2 mRNA levels (in lymphoblastoid cells) and that increased GAB2 mRNA levels are associated with significantly decreased LOAD pathology. These findings support the hypothesis that Gab2 may protect neurons against LOAD but due to significant population heterogeneity, it is still unclear whether this protection is detectable at the genetic level.

Original languageEnglish (US)
Article numbere64802
JournalPLoS One
Volume8
Issue number5
DOIs
StatePublished - May 28 2013

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Pathology
Alzheimer disease
binding proteins
Carrier Proteins
Alzheimer Disease
odds ratio
Odds Ratio
Messenger RNA
Meta-Analysis
Disease control
Neurofibrillary Tangles
Amyloid Plaques
Population Characteristics
Population
Neurons
Brain
disease control
Genes
neurons
Cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Linking Protective GAB2 Variants, Increased Cortical GAB2 Expression and Decreased Alzheimer's Disease Pathology. / Zou, Fanggeng; Belbin, Olivia; Carrasquillo, Minerva M; Culley, Oliver J.; Hunter, Talisha A.; Ma, Li; Bisceglio, Gina D.; Allen, Mariet; Dickson, Dennis W; Graff Radford, Neill R; Petersen, Ronald Carl; Morgan, Kevin; Younkin, Steven G.

In: PLoS One, Vol. 8, No. 5, e64802, 28.05.2013.

Research output: Contribution to journalArticle

Zou, Fanggeng ; Belbin, Olivia ; Carrasquillo, Minerva M ; Culley, Oliver J. ; Hunter, Talisha A. ; Ma, Li ; Bisceglio, Gina D. ; Allen, Mariet ; Dickson, Dennis W ; Graff Radford, Neill R ; Petersen, Ronald Carl ; Morgan, Kevin ; Younkin, Steven G. / Linking Protective GAB2 Variants, Increased Cortical GAB2 Expression and Decreased Alzheimer's Disease Pathology. In: PLoS One. 2013 ; Vol. 8, No. 5.
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AU - Hunter, Talisha A.

AU - Ma, Li

AU - Bisceglio, Gina D.

AU - Allen, Mariet

AU - Dickson, Dennis W

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