GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers.

TitleGAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers.
Publication TypeJournal Article
Year of Publication2007
AuthorsReiman, EM, Webster, JA, Myers, AJ, Hardy, J, Dunckley, T, Zismann, VL, Joshipura, KD, Pearson, JV, Hu-Lince, D, Huentelman, MJ, Craig, DW, Coon, KD, Liang, WS, Herbert, RLH, Beach, T, Rohrer, KC, Zhao, AS, Leung, D, Bryden, L, Marlowe, L, Kaleem, M, Mastroeni, D, Grover, A, Heward, CB, Ravid, R, Rogers, J, Hutton, ML, Melquist, S, Petersen, RC, Alexander, GE, Caselli, RJ, Kukull, W, Papassotiropoulos, A, Stephan, DA
JournalNeuron
Volume54
Issue5
Pagination713-20
Date Published2007 Jun 07
ISSN0896-6273
KeywordsAdaptor Proteins, Signal Transducing, Alzheimer Disease, Apolipoprotein E4, Brain, Brain Chemistry, Cell Line, Tumor, DNA Mutational Analysis, Gene Expression Regulation, Gene Frequency, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Haplotypes, Humans, Mutation, Neurofibrillary Tangles, Phosphorylation, Polymorphism, Single Nucleotide, Risk Factors, tau Proteins
Abstract

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.

DOI10.1016/j.neuron.2007.05.022
Alternate JournalNeuron
PubMed ID17553421
PubMed Central IDPMC2587162
Grant ListP50 AG16574 / AG / NIA NIH HHS / United States
P50 MH060451 / MH / NIMH NIH HHS / United States
P50 AG17824 / AG / NIA NIH HHS / United States
P50 AG08671 / AG / NIA NIH HHS / United States
P50 AG 05681 / AG / NIA NIH HHS / United States
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P50 AG05136 / AG / NIA NIH HHS / United States
P50 AG16570 / AG / NIA NIH HHS / United States
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U24NS051872 / NS / NINDS NIH HHS / United States
P50 AG005128 / AG / NIA NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
P50 AG005146 / AG / NIA NIH HHS / United States
U01HL084744 / HL / NHLBI NIH HHS / United States
G0701075 / / Medical Research Council / United Kingdom
P50 AG05146 / AG / NIA NIH HHS / United States
P50 AG05142 / AG / NIA NIH HHS / United States
U24 NS051872 / NS / NINDS NIH HHS / United States
K01 AG024079 / AG / NIA NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
P30 AG017824 / AG / NIA NIH HHS / United States
R21 AG029576-01 / AG / NIA NIH HHS / United States
R01 MH60451 / MH / NIMH NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
P50 NS039764 / NS / NINDS NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
P30 AG013846 / AG / NIA NIH HHS / United States
K01 AG024079-01A2 / AG / NIA NIH HHS / United States
P30 AG10161 / AG / NIA NIH HHS / United States
P50 AG05134 / AG / NIA NIH HHS / United States
P50 AG005136 / AG / NIA NIH HHS / United States
P30 AG012300 / AG / NIA NIH HHS / United States
R01 AG23193 / AG / NIA NIH HHS / United States
K01AG024079 / AG / NIA NIH HHS / United States
K01 AG024079-02 / AG / NIA NIH HHS / United States
/ / Intramural NIH HHS / United States
P50 AG016570 / AG / NIA NIH HHS / United States
P50 AG005134 / AG / NIA NIH HHS / United States
R01 NS39764 / NS / NINDS NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
P50 AG05144 / AG / NIA NIH HHS / United States
AG025688 / AG / NIA NIH HHS / United States
P50 AG025688 / AG / NIA NIH HHS / United States
P50 AG005144 / AG / NIA NIH HHS / United States
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P30 AG19610 / AG / NIA NIH HHS / United States
P50 AG08702 / AG / NIA NIH HHS / United States
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