@article{76f4ccbdf64f47a8bb31b73106681f90,
title = "GAB2 Alleles Modify Alzheimer's Risk in APOE ε4 Carriers",
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.",
keywords = "HUMDISEASE, MOLNEURO",
author = "Reiman, {Eric M.} and Webster, {Jennifer A.} and Myers, {Amanda J.} and John Hardy and Travis Dunckley and Zismann, {Victoria L.} and Joshipura, {Keta D.} and Pearson, {John V.} and Diane Hu-Lince and Huentelman, {Matthew J J.} and Craig, {David W.} and Coon, {Keith D.} and Liang, {Winnie S.} and Herbert, {Ri Lee H.} and Thomas Beach and Rohrer, {Kristen C.} and Zhao, {Alice S.} and Doris Leung and Leslie Bryden and Lauren Marlowe and Mona Kaleem and Diego Mastroeni and Andrew Grover and Heward, {Christopher B.} and Rivka Ravid and Joseph Rogers and Hutton, {Michael L.} and Stacey Melquist and Petersen, {Ron C.} and Alexander, {Gene E.} and Caselli, {Richard J J.} and Walter Kukull and Andreas Papassotiropoulos and Stephan, {Dietrich A.}",
note = "Funding Information: These studies were supported by Kronos Life Sciences Laboratories, the National Institute on Aging (Arizona Alzheimer's Disease Center P30 AG19610, RO1 AG023193, Mayo Clinic Alzheimer's Disease Center P50 AG16574, and Intramural Research Program), the National Alzheimer's Coordinating Center (U01 AG016976), and the state of Arizona. We thank our research volunteers and their families for their generous participation; Drs. Creighton Phelps, Marcelle Morrison-Bogorad, Marilyn Miller, and Walter Kukull for their assistance in the acquisition of tissue samples and data; and directors, pathologists, and technologists from the following ADCs and brain banks: Lucia Sue (Sun Health Research Institute and Arizona Alzheimer's Disease Center); Ruth Seemann and Dan Brady (National Institute on Aging); Juan C. Troncoso and Olga Pletnikova (John Hopkins, P50 AG05146); Harry Vinters and Justine Pomakian (University of California, Los Angeles, P50 AG16570); Christine Hulette (The Kathleen Price Bryan Brain Bank, Duke University Medical Center, P50 AG05128, RO1 NS39764, RO1 MH60451, and GlaxoSmithKline); Dikran Horoupian and Ahmad Salehi (Stanford University, P30 AG17824); Jean Paul Vonsattel (New York Brain Bank, Taub Institute, Columbia University, P50 AG08702); E. Tessa Hedley-Whyte and Karlotta Fitch (Massachusetts General Hospital, P50 AG05134); Roger Albin, Lisa Bain, and Eszter Gombosi (University of Michigan, P50 AG08671); William Markesbery, Sonya Anderson (University of Kentucky, P50 AG05144); Dennis W. Dickson and Natalie Thomas (Mayo Clinic, Jacksonville, P50 AG16574 and P50 AG25711); Carol A. Miller, Jenny Tang, and Dimitri Diaz (University of Southern California, P50 AG05142); Dan McKeel, John C. Morris, Eugene Johnson, Jr., Virginia Buckles, and Deborah Carter (Washington University, St. Louis, P50 AG 05681); Thomas Montine and Aimee Schantz (University of Washington, P50 AG05136); John Q. Trojanowski, Virginia M. Lee, Vivianna Van Deerlin, and Terry Schuck (University of Pennsylvania); Ann C. McKee and Carol Kubilus (Boston University, P30 AG13846); Bruce H. Wainer and Marla Gearing (Emory University, AG025688); Charles L. White III, Roger Rosenberg, Marilyn Howell, and Joan Reisch (University of Texas, Southwestern Medical School, P30-AG12300); William Ellis and Mary Ann Jarvis (University of California, Davis, P30 AG AG01542); David A. Bennett, Julie A. Schneider, Karen Skish, and Wayne T. Longman (Rush University Medical Center, P30 AG10161); and Deborah C. Mash, Margaret J. Basile, and Mitsuko Tanaka University of Miami/NPF Brain Endowment Bank). Additional support was provided by the Johnnie B. Byrd Sr. Alzheimer's Disease and Research Institute, the Swiss National Science Foundation (PP00B-68859), the Verum foundation, the Bisgrove charitable donation, the NIH Neuroscience Blueprint (U24NS051872), the ENDGAME Consortium (UO1HL084744), and the National Institute on Aging (K01AG024079).",
year = "2007",
month = jun,
day = "7",
doi = "10.1016/j.neuron.2007.05.022",
language = "English (US)",
volume = "54",
pages = "713--720",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "5",
}