GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers.
The apolipoprotein E (APOE) epsilon4 allele is the best established genetic risk factor for late-onset Alzheimer's disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In epsilon4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 x 10(-11)) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts with APOE epsilon4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE epsilon4 carriers and influences Alzheimer's neuropathology.
Reiman
Eric M
EM
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA. eric.reiman@bannerhealth.com
Webster
Jennifer A
JA
Myers
Amanda J
AJ
Hardy
John
J
Dunckley
Travis
T
Zismann
Victoria L
VL
Joshipura
Keta D
KD
Pearson
John V
JV
Hu-Lince
Diane
D
Huentelman
Matthew J
MJ
Craig
David W
DW
Coon
Keith D
KD
Liang
Winnie S
WS
Herbert
RiLee H
RH
Beach
Thomas
T
Rohrer
Kristen C
KC
Zhao
Alice S
AS
Leung
Doris
D
Bryden
Leslie
L
Marlowe
Lauren
L
Kaleem
Mona
M
Mastroeni
Diego
D
Grover
Andrew
A
Heward
Christopher B
CB
Ravid
Rivka
R
Rogers
Joseph
J
Hutton
Michael L
ML
Melquist
Stacey
S
Petersen
Ron C
RC
Alexander
Gene E
GE
Caselli
Richard J
RJ
Kukull
Walter
W
Papassotiropoulos
Andreas
A
Stephan
Dietrich A
DA
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D053327:Apolipoprotein E4 / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D005786:Gene Expression Regulation / Q000235:genetics; D005787:Gene Frequency; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D009154:Mutation; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D016875:tau Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D053327:Apolipoprotein E4; C490895:GAB2 protein, human; D005819:Genetic Markers; D016875:tau Proteins