| Literature DB >> 17553421 |
Eric M Reiman1, Jennifer A Webster, Amanda J Myers, John Hardy, Travis Dunckley, Victoria L Zismann, Keta D Joshipura, John V Pearson, Diane Hu-Lince, Matthew J Huentelman, David W Craig, Keith D Coon, Winnie S Liang, RiLee H Herbert, Thomas Beach, Kristen C Rohrer, Alice S Zhao, Doris Leung, Leslie Bryden, Lauren Marlowe, Mona Kaleem, Diego Mastroeni, Andrew Grover, Christopher B Heward, Rivka Ravid, Joseph Rogers, Michael L Hutton, Stacey Melquist, Ron C Petersen, Gene E Alexander, Richard J Caselli, Walter Kukull, Andreas Papassotiropoulos, Dietrich A Stephan.
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.Entities:
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Year: 2007 PMID： 17553421 PMCID： PMC2587162 DOI： 10.1016/j.neuron.2007.05.022
Source DB: PubMed Journal: Neuron ISSN： 0896-6273 Impact factor: 17.173