title: Genetic association of the APP binding protein 2 gene (APBB2) with late onset Alzheimer disease.
abstract: Alzheimer disease (AD) is a complex neurodegenerative disorder predisposed by multiple genetic factors. Mutations in amyloid beta precursor protein (APP) are known to be associated with autosomal dominant, early onset familial AD and possibly also late onset AD (LOAD). A number of genes encoding proteins capable of binding to APP have been identified, but their contribution to AD pathobiology remains unclear. Conceivably, mutations in these genes may play a role in affecting AD susceptibility, which appears to be substantiated by some genetic studies. Here we report results of the first genetic association study with APBB2, an APP binding protein (also known as FE65L), and LOAD, in three independently collected case-control series totaling approximately 2,000 samples. Two SNPs were significantly associated with LOAD in two sample series and in meta-analyses of all three sample sets (for rs13133980: odds ratio [OR](hom)=1.36 [95% CI: 1.05-1.75], OR(het)=1.32 [95% CI: 1.04-1.67], minor allele frequency=43%, P=0.041; and for hCV1558625: OR(hom)=1.37 [95% CI: 1.06-1.77], OR(het)=1.02 [95% CI: 0.82-1.26], minor allele frequency=48%, P=0.026). One of these SNPs, located in a region conserved between the human and mouse genome, showed a significant interaction with age of disease onset. For this marker, the association with LOAD was most pronounced in subjects with disease onset before 75 years of age (OR(hom)=2.43 [95% CI: 1.61-3.67]; OR(het)=2.15 [95% CI: 1.46-3.17]; P=0.00006) in the combined sample set. Our data raise the possibility that genetic variations in APBB2 may affect LOAD susceptibility.
authors.affiliation: Celera Diagnostics, Alameda, California 94502, USA.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Li
authors.forename: Paul
authors.initials: P
authors.lastname: Hollingworth
authors.forename: Pamela
authors.initials: P
authors.lastname: Moore
authors.forename: Catherine
authors.initials: C
authors.lastname: Foy
authors.forename: Nicola
authors.initials: N
authors.lastname: Archer
authors.forename: John
authors.initials: J
authors.lastname: Powell
authors.forename: Petra
authors.initials: P
authors.lastname: Nowotny
authors.forename: Peter
authors.initials: P
authors.lastname: Holmans
authors.forename: Michael
authors.initials: M
authors.lastname: O'Donovan
authors.forename: Kristina
authors.initials: K
authors.lastname: Tacey
authors.forename: Lisa
authors.initials: L
authors.lastname: Doil
authors.forename: Ryan
authors.initials: R
authors.lastname: van Luchene
authors.forename: Veronica
authors.initials: V
authors.lastname: Garcia
authors.forename: Charles
authors.initials: C
authors.lastname: Rowland
authors.forename: Kit
authors.initials: K
authors.lastname: Lau
authors.forename: Joseph
authors.initials: J
authors.lastname: Cantanese
authors.forename: John
authors.initials: J
authors.lastname: Sninsky
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Leon
authors.initials: L
authors.lastname: Thal
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.forename: Michael
authors.initials: M
authors.lastname: Owen
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
authors.forename: Andrew
authors.initials: A
authors.lastname: Grupe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000502:physiology; D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D014481:United States / Q000453:epidemiology; D014852:Wales / Q000453:epidemiology
chemical_list: C466684:APBB2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D053327:Apolipoprotein E4; D001057:Apolipoproteins E