Genetic association of the APP binding protein 2 gene (APBB2) with late onset Alzheimer disease

Yonghong Li, Paul Hollingworth, Pamela Moore, Catherine Foy, Nicola Archer, John Powell, Petra Nowotny, Peter Holmans, Michael O'Donovan, Kristina Tacey, Lisa Doil, Ryan Van Luchene, Veronica Garcia, Charles Rowland, Kit Lau, Joseph Cantanese, John Sninsky, John Hardy, Leon Thal, John C. MorrisAlison Goate, Simon Lovestone, Michael Owen, Julie Williams, Andrew Grupe

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Alzheimer disease (AD) is a complex neurodegenerative disorder predisposed by multiple genetic factors. Mutations in amyloid β 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], ORhet = 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], ORhet = 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 (ORhom = 2.43 [95% CI: 1.61-3.67]; ORhet = 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.

Original languageEnglish
Pages (from-to)270-277
Number of pages8
JournalHuman mutation
Volume25
Issue number3
DOIs
StatePublished - Mar 29 2005

Keywords

  • AD
  • APBB2
  • APP
  • Alzheimer disease
  • Association
  • LOAD
  • SNP

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    Li, Y., Hollingworth, P., Moore, P., Foy, C., Archer, N., Powell, J., Nowotny, P., Holmans, P., O'Donovan, M., Tacey, K., Doil, L., Van Luchene, R., Garcia, V., Rowland, C., Lau, K., Cantanese, J., Sninsky, J., Hardy, J., Thal, L., ... Grupe, A. (2005). Genetic association of the APP binding protein 2 gene (APBB2) with late onset Alzheimer disease. Human mutation, 25(3), 270-277. https://doi.org/10.1002/humu.20138