Dataset Information

Linking protective GAB2 variants, increased cortical GAB2 expression and decreased Alzheimer's disease pathology.

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.

SUBMITTER: Zou F

PROVIDER: S-EPMC3665686 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Linking protective GAB2 variants, increased cortical GAB2 expression and decreased Alzheimer's disease pathology.

Zou Fanggeng F Belbin Olivia O Belbin Olivia O Carrasquillo Minerva M MM Culley Oliver J OJ Hunter Talisha A TA Ma Li L Bisceglio Gina D GD Allen Mariet M Dickson Dennis W DW Graff-Radford Neill R NR Petersen Ronald C RC Morgan Kevin K Younkin Steven G SG

PloS one 20130528 5

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) du ...[more]

PMID: 23724096

Similar Datasets

Project description:BackgroundAlzheimer's Disease (AD) is an age-related neurodegenerative disease with a poorly understood etiology, shown to be partly genetic. Glucose hypometabolism, extracellular Amyloid-beta (Aβ) deposition, and intracellular Tau deposition are cardinal features of AD and display characteristic spatial patterns in the brain. We hypothesize that regional differences in underlying gene expression confer either resistance or susceptibility to AD pathogenic processes and are associated with these spatial patterns. Data-driven methods for the identification of genes involved in AD pathogenesis complement hypothesis-driven approaches that reflect current theories about the disease. Here we present a data driven method for the identification of genes involved in AD pathogenesis based on comparing spatial patterns of normal gene expression to Positron Emission Tomography (PET) images of glucose hypometabolism, Aβ deposition, and Tau deposition.MethodsWe performed correlations between the cerebral cortex microarray samples from the six cognitively normal (CN) post-mortem Allen Human Brain Atlas (AHBA) specimens and PET FDG-18, AV-45, and AV-1451 tracer images from AD and CN participants in the Alzheimer's Disease and Neuroimaging Initiative (ADNI) database. Correlation coefficients for each gene by each ADNI subject were then entered into a partial least squares discriminant analysis (PLS-DA) to determine sets that best classified the AD and CN groups. Pathway analysis via BioPlanet 2019 was then used to infer the function of implicated genes.ResultsWe identified distinct sets of genes strongly associated with each PET modality. Pathway analyses implicated novel genes involved in mitochondrial function, and Notch signaling, as well as genes previously associated with AD.ConclusionUsing an unbiased approach, we derived sets of genes with expression patterns spatially associated with FDG hypometabolism, Aβ deposition, and Tau deposition in AD. This methodology may complement population-based approaches for identifying the genetic underpinnings of AD.

Dataset Information

Linking protective GAB2 variants, increased cortical GAB2 expression and decreased Alzheimer's disease pathology.

Publications

Linking protective GAB2 variants, increased cortical GAB2 expression and decreased Alzheimer's disease pathology.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets