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GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers

Reiman, Eric M. and Webster, Jennifer A. and Myers, Amanda J. and Hardy, John and Dunckley, Travis and Zismann, Victoria L. and Joshipura, Keta D. and Pearson, John V. and Hu-Lince, Diane and Huentelman, Matthew J. and Craig, David W. and Coon, Keith D. and Liang, Winnie S. and Herbert, RiLee H. and Beach, Thomas and Rohrer, Kristen C. and Zhao, Alice S. and Leung, Doris and Bryden, Leslie and Marlowe, Lauren and Kaleem, Mona and Mastroeni, Diego and Grover, Andrew and Heward, Christopher B. and Ravid, Rivka and Rogers, Joseph and Hutton, Michael L. and Melquist, Stacey and Petersen, Ron C. and Alexander, Gene E. and Caselli, Richard J. and Kukull, Walter and Papassotiropoulos, Andreas and Stephan, Dietrich A.. (2007) GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers. Neuron, Vol. 54, H. 5. pp. 713-720.

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Official URL: http://edoc.unibas.ch/dok/A5257153

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Services Biozentrum > Life Sciences Training Facility (Papassotiropoulos)
07 Faculty of Psychology > Departement Psychologie > Forschungsbereich Klinische Psychologie und Neurowissenschaften > Molecular Psychology (Papassotiropoulos)
UniBasel Contributors:Papassotiropoulos, Andreas
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Cell Press
ISSN:0896-6273
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:22 Mar 2012 14:19
Deposited On:22 Mar 2012 13:17

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