GAB2 Alleles Modify Alzheimer's Risk in APOE ε4 Carriers

Eric M. Reiman, 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 & 14 others 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

Research output: Contribution to journalArticle

390 Citations (Scopus)

Abstract

The apolipoprotein E (APOE) ε4 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 ε4 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 × 10-11) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts with APOE ε4 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 ε4 carriers and influences Alzheimer's neuropathology.

Original languageEnglish
Pages (from-to)713-720
Number of pages8
JournalNeuron
Volume54
Issue number5
DOIs
StatePublished - Jun 7 2007

Fingerprint

Apolipoprotein E4
Carrier Proteins
Alleles
Single Nucleotide Polymorphism
Alzheimer Disease
Neurons
Genes
Neuritis
Disease Susceptibility
Haplotypes
Odds Ratio
Phosphorylation
Genome
Confidence Intervals
Gene Expression
Proteins

Keywords

  • HUMDISEASE
  • MOLNEURO

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Reiman, E. M., Webster, J. A., Myers, A. J., Hardy, J., Dunckley, T., Zismann, V. L., ... Stephan, D. A. (2007). GAB2 Alleles Modify Alzheimer's Risk in APOE ε4 Carriers. Neuron, 54(5), 713-720. https://doi.org/10.1016/j.neuron.2007.05.022

GAB2 Alleles Modify Alzheimer's Risk in APOE ε4 Carriers. / Reiman, Eric M.; Webster, Jennifer A.; Myers, Amanda J; Hardy, John; Dunckley, Travis; Zismann, Victoria L.; Joshipura, Keta D.; Pearson, John V.; Hu-Lince, Diane; Huentelman, Matthew J; Craig, David W.; Coon, Keith D.; Liang, Winnie S.; Herbert, RiLee H.; Beach, Thomas; Rohrer, Kristen C.; Zhao, Alice S.; Leung, Doris; Bryden, Leslie; Marlowe, Lauren; Kaleem, Mona; Mastroeni, Diego; Grover, Andrew; Heward, Christopher B.; Ravid, Rivka; Rogers, Joseph; Hutton, Michael L.; Melquist, Stacey; Petersen, Ron C.; Alexander, Gene E.; Caselli, Richard J; Kukull, Walter; Papassotiropoulos, Andreas; Stephan, Dietrich A.

In: Neuron, Vol. 54, No. 5, 07.06.2007, p. 713-720.

Research output: Contribution to journalArticle

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 & Stephan, DA 2007, 'GAB2 Alleles Modify Alzheimer's Risk in APOE ε4 Carriers', Neuron, vol. 54, no. 5, pp. 713-720. https://doi.org/10.1016/j.neuron.2007.05.022
Reiman EM, Webster JA, Myers AJ, Hardy J, Dunckley T, Zismann VL et al. GAB2 Alleles Modify Alzheimer's Risk in APOE ε4 Carriers. Neuron. 2007 Jun 7;54(5):713-720. https://doi.org/10.1016/j.neuron.2007.05.022
Reiman, Eric M. ; Webster, Jennifer A. ; Myers, Amanda J ; Hardy, John ; Dunckley, Travis ; Zismann, Victoria L. ; Joshipura, Keta D. ; Pearson, John V. ; Hu-Lince, Diane ; Huentelman, Matthew J ; Craig, David W. ; Coon, Keith D. ; Liang, Winnie S. ; Herbert, RiLee H. ; Beach, Thomas ; Rohrer, Kristen C. ; Zhao, Alice S. ; Leung, Doris ; Bryden, Leslie ; Marlowe, Lauren ; Kaleem, Mona ; Mastroeni, Diego ; Grover, Andrew ; Heward, Christopher B. ; Ravid, Rivka ; Rogers, Joseph ; Hutton, Michael L. ; Melquist, Stacey ; Petersen, Ron C. ; Alexander, Gene E. ; Caselli, Richard J ; Kukull, Walter ; Papassotiropoulos, Andreas ; Stephan, Dietrich A. / GAB2 Alleles Modify Alzheimer's Risk in APOE ε4 Carriers. In: Neuron. 2007 ; Vol. 54, No. 5. pp. 713-720.
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AU - Craig, David W.

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AU - Hutton, Michael L.

AU - Melquist, Stacey

AU - Petersen, Ron C.

AU - Alexander, Gene E.

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N2 - The apolipoprotein E (APOE) ε4 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 ε4 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 × 10-11) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts with APOE ε4 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 ε4 carriers and influences Alzheimer's neuropathology.

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