title: Association studies testing for risk for late-onset Alzheimer's disease with common variants in the beta-amyloid precursor protein (APP).
abstract: Linkage studies have suggested a susceptibility locus for late-onset Alzheimer's disease (LOAD) on chromosome 21. A functional candidate gene in this region is the beta-amyloid precursor protein (APP) gene. Previously, coding mutations in APP have been associated with early onset Alzheimer's Disease (EOAD). Three copies of APP are associated with AD pathology in Down's syndrome and in EOAD, suggesting that overexpression of APP may be a risk factor for LOAD. Although APP is a strong functional and positional candidate, to date there has been no thorough investigation using a dense map of SNPs across the APP gene. In order to investigate the role of common variation in the APP gene in the risk of LOAD, we genotyped 44 SNPs, spanning 300 kb spanning the entire gene, in a large case-control series of 738 AD cases and 657 healthy controls. The SNPs showed no association in genotypic or allelic tests, even after stratification for presence or absence of the APOE 4 allele. Haplotype analysis also failed to reveal significant association with any common haplotypes. These results suggest that common variation in the APP gene is not a significant risk factor for LOAD. However, we cannot rule out the possibility that multiple rare variants that increase APP expression or Abeta production might influence the risk for LOAD.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Petra
authors.initials: P
authors.lastname: Nowotny
authors.forename: Xavier
authors.initials: X
authors.lastname: Simcock
authors.forename: Sarah
authors.initials: S
authors.lastname: Bertelsen
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Hinrichs
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
authors.forename: Kevin
authors.initials: K
authors.lastname: Mayo
authors.forename: Scott
authors.initials: S
authors.lastname: Smemo
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000453:epidemiology* / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D014481:United States / Q000453:epidemiology
chemical_list: D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E