title: Chromosome 21 BACE2 haplotype associates with Alzheimer's disease: a two-stage study.
abstract: Genetic linkage studies have provided evidence for a late-onset Alzheimer's disease (AD) susceptibility locus on chromosome 21q. We have tested, in a two-stage association study, whether allelic or haplotype variation of the beta-amyloid cleaving enzyme-2 (BACE2) locus on chromosome 21q affects the risk of late-onset AD. In stage-1, an unselected population-based sample of Finns aged 85 years or over (n=515) was analysed. Neuropathologic examination including beta-amyloid load quantification was possible in over 50% (n=264) of these subjects. AD patients (n=100) and controls (n=48) were defined by modified neuropathological NIA-RI criteria. Positive associations were taken as a hypothesis, and tested in stage-2 using 483 AD families from the USA. Four single nucleotide polymorphisms (SNPs) of BACE2 gene were tested in stage-1. A SNP close to exon-6 was associated with neuropathologically verified AD (p=0.02) and also with beta-amyloid load in non-selected autopsied subjects after conditioning with APOE genotype (p=0.001). In haplotype analysis a specific, relatively common haplotype (H5) was found to associate with AD (p=0.004) and a second haplotype (H7) showed a weaker association with protection against AD (p=0.04). In stage-2, the SNP association was not replicated, whereas the haplotype H5 association was replicated (p=0.004) and a trend to association was found with the putative protective haplotype H7 (two-sided p=0.08). BACE2 haplotype association with AD in two independent datasets provides further evidence for an AD susceptibility locus on chromosome 21q within or close to BACE2.
authors: Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland.
authors: Liisa
authors: L
authors: Myllykangas
authors: Fabienne
authors: F
authors: Wavrant-De Vrièze
authors: Tuomo
authors: T
authors: Polvikoski
authors: Irma-Leena
authors: IL
authors: Notkola
authors: Raimo
authors: R
authors: Sulkava
authors: Leena
authors: L
authors: Niinistö
authors: Steven D
authors: SD
authors: Edland
authors: Sampath
authors: S
authors: Arepalli
authors: Omanma
authors: O
authors: Adighibe
authors: Danielle
authors: D
authors: Compton
authors: John
authors: J
authors: Hardy
authors: Matti
authors: M
authors: Haltia
authors: Pentti J
authors: PJ
authors: Tienari
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases; D001057:Apolipoproteins E / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D016009:Chi-Square Distribution; D002891:Chromosomes, Human, Pair 21; D019992:Databases as Topic; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D009460:Neurologic Examination / Q000379:methods; D020641:Polymorphism, Single Nucleotide
chemical_list: D001057:Apolipoproteins E; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases