1. GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers.
- Author
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Reiman 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 RH, 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, and Stephan DA
- Subjects
- Brain metabolism, Brain pathology, Brain physiopathology, Brain Chemistry genetics, Cell Line, Tumor, DNA Mutational Analysis, Gene Expression Regulation genetics, Gene Frequency, Genetic Markers genetics, Genetic Testing, Haplotypes genetics, Humans, Mutation, Neurofibrillary Tangles genetics, Neurofibrillary Tangles metabolism, Neurofibrillary Tangles pathology, Phosphorylation, Risk Factors, tau Proteins metabolism, Adaptor Proteins, Signal Transducing genetics, Alzheimer Disease genetics, Alzheimer Disease metabolism, Apolipoprotein E4 genetics, Genetic Predisposition to Disease genetics, Polymorphism, Single Nucleotide genetics
- 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.
- Published
- 2007
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