title: GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers.
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.
authors.affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA. eric.reiman@bannerhealth.com
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Webster
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Myers
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Travis
authors.initials: T
authors.lastname: Dunckley
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Zismann
authors.forename: Keta D
authors.initials: KD
authors.lastname: Joshipura
authors.forename: John V
authors.initials: JV
authors.lastname: Pearson
authors.forename: Diane
authors.initials: D
authors.lastname: Hu-Lince
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.forename: David W
authors.initials: DW
authors.lastname: Craig
authors.forename: Keith D
authors.initials: KD
authors.lastname: Coon
authors.forename: Winnie S
authors.initials: WS
authors.lastname: Liang
authors.forename: RiLee H
authors.initials: RH
authors.lastname: Herbert
authors.forename: Thomas
authors.initials: T
authors.lastname: Beach
authors.forename: Kristen C
authors.initials: KC
authors.lastname: Rohrer
authors.forename: Alice S
authors.initials: AS
authors.lastname: Zhao
authors.forename: Doris
authors.initials: D
authors.lastname: Leung
authors.forename: Leslie
authors.initials: L
authors.lastname: Bryden
authors.forename: Lauren
authors.initials: L
authors.lastname: Marlowe
authors.forename: Mona
authors.initials: M
authors.lastname: Kaleem
authors.forename: Diego
authors.initials: D
authors.lastname: Mastroeni
authors.forename: Andrew
authors.initials: A
authors.lastname: Grover
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Heward
authors.forename: Rivka
authors.initials: R
authors.lastname: Ravid
authors.forename: Joseph
authors.initials: J
authors.lastname: Rogers
authors.forename: Michael L
authors.initials: ML
authors.lastname: Hutton
authors.forename: Stacey
authors.initials: S
authors.lastname: Melquist
authors.forename: Ron C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Gene E
authors.initials: GE
authors.lastname: Alexander
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Caselli
authors.forename: Walter
authors.initials: W
authors.lastname: Kukull
authors.forename: Andreas
authors.initials: A
authors.lastname: Papassotiropoulos
authors.forename: Dietrich A
authors.initials: DA
authors.lastname: Stephan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D053327:Apolipoprotein E4 / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D005786:Gene Expression Regulation / Q000235:genetics; D005787:Gene Frequency; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D009154:Mutation; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D016875:tau Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053327:Apolipoprotein E4; C490895:GAB2 protein, human; D005819:Genetic Markers; D016875:tau Proteins