Association studies testing for risk for late-onset Alzheimer's disease with common variants in the β-amyloid precursor protein (APP)

• Published in: American journal of medical genetics. Part B, Neuropsychiatric genetics Neuropsychiatric genetics, 2007-06, Vol.144B (4), p.469-474
• Main Authors: Nowotny, Petra, Simcock, Xavier, Bertelsen, Sarah, Hinrichs, Anthony L., Kauwe, John S.K., Mayo, Kevin, Smemo, Scott, Morris, John C., Goate, Alison
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Age of Onset; Aged; Aged, 80 and over; Alleles; Alzheimer Disease - epidemiology; Alzheimer Disease - genetics; Alzheimer's disease (AD); Amyloid beta-Protein Precursor - genetics; Apolipoproteins E - genetics; association analysis; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Linkage Disequilibrium - genetics; Male; Medical genetics; Medical sciences; Middle Aged; Neurology; Organic mental disorders. Neuropsychology; Polymorphism, Single Nucleotide - genetics; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Risk Factors; single nucleotide polymorphism (SNP); United States - epidemiology; β-amyloid precursor protein (APP)
• ISSN: 1552-4841; 1552-485X
• DOI: 10.1002/ajmg.b.30485

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 β‐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 ϵ4 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 Aβ production might influence the risk for LOAD. © 2007 Wiley‐Liss, Inc.