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

TY - JOUR

T1 - Linking protective GAB2 variants, increased cortical GAB2 expression and decreased Alzheimer's disease pathology

AU - Zou, Fanggeng

AU - Belbin, Olivia

AU - Carrasquillo, Minerva M

AU - Culley, Oliver J

AU - Hunter, Talisha A

AU - Ma, Li

AU - Bisceglio, Gina D

AU - Allen, Mariet

AU - Dickson, Dennis W

AU - Graff-Radford, Neill R

AU - Petersen, Ronald C

AU - Morgan, Kevin

AU - Younkin, Steven G

AU - Genetic and Environmental Risk for Alzheimer’s disease (GERAD1) Consortium

AU - Bussche van den, Hendrik

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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.

AB - 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.

KW - Adaptor Proteins, Signal Transducing

KW - Aged

KW - Alzheimer Disease

KW - Apolipoproteins E

KW - Case-Control Studies

KW - Cell Line

KW - Epistasis, Genetic

KW - Female

KW - Genetic Association Studies

KW - Genetic Heterogeneity

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Haplotypes

KW - Humans

KW - Male

KW - Meta-Analysis as Topic

KW - North America

KW - Polymorphism, Single Nucleotide

KW - Postmortem Changes

KW - RNA, Messenger

KW - Risk Factors

KW - Temporal Lobe

U2 - 10.1371/journal.pone.0064802

DO - 10.1371/journal.pone.0064802

M3 - SCORING: Journal article

C2 - 23724096

VL - 8

SP - e64802

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 5

ER -