Chromosome 21 BACE2 haplotype associates with Alzheimer's disease: a two-stage study

Liisa Myllykangas, Fabienne Wavrant-De Vrieze, Tuomo Polvikoski, Irma-Leena Notkola, Raimo Sulkava, Leena Niinistö, Steven D Edland, Sampath Arepalli, Omanma Adighibe, Danielle Compton, John Hardy, Matti Haltia, Pentti J Tienari

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Kuvaus

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. (c) 2005 Elsevier B.V. All rights reserved.
Alkuperäiskielienglanti
LehtiJournal of the Neurological Sciences
Vuosikerta236
Sivut17-24
Sivumäärä8
ISSN0022-510X
DOI - pysyväislinkit
TilaJulkaistu - 2005
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Lainaa tätä

Myllykangas, Liisa ; Wavrant-De Vrieze, Fabienne ; Polvikoski, Tuomo ; Notkola, Irma-Leena ; Sulkava, Raimo ; Niinistö, Leena ; Edland, Steven D ; Arepalli, Sampath ; Adighibe, Omanma ; Compton, Danielle ; Hardy, John ; Haltia, Matti ; Tienari, Pentti J. / Chromosome 21 BACE2 haplotype associates with Alzheimer's disease : a two-stage study. Julkaisussa: Journal of the Neurological Sciences. 2005 ; Vuosikerta 236. Sivut 17-24.
@article{7cce62dff8fb4d5ab980be8d664036b4,
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. (c) 2005 Elsevier B.V. All rights reserved.",
author = "Liisa Myllykangas and {Wavrant-De Vrieze}, Fabienne and Tuomo Polvikoski and Irma-Leena Notkola and Raimo Sulkava and Leena Niinist{\"o} and Edland, {Steven D} and Sampath Arepalli and Omanma Adighibe and Danielle Compton and John Hardy and Matti Haltia and Tienari, {Pentti J}",
year = "2005",
doi = "10.1016/j.jns.2005.04.008",
language = "English",
volume = "236",
pages = "17--24",
journal = "Journal of the Neurological Sciences",
issn = "0022-510X",
publisher = "Elsevier Scientific Publ. Co",

}

Myllykangas, L, Wavrant-De Vrieze, F, Polvikoski, T, Notkola, I-L, Sulkava, R, Niinistö, L, Edland, SD, Arepalli, S, Adighibe, O, Compton, D, Hardy, J, Haltia, M & Tienari, PJ 2005, 'Chromosome 21 BACE2 haplotype associates with Alzheimer's disease: a two-stage study', Journal of the Neurological Sciences, Vuosikerta 236, Sivut 17-24. https://doi.org/10.1016/j.jns.2005.04.008

Chromosome 21 BACE2 haplotype associates with Alzheimer's disease : a two-stage study. / Myllykangas, Liisa; Wavrant-De Vrieze, Fabienne; Polvikoski, Tuomo; Notkola, Irma-Leena; Sulkava, Raimo; Niinistö, Leena; Edland, Steven D; Arepalli, Sampath; Adighibe, Omanma; Compton, Danielle; Hardy, John; Haltia, Matti; Tienari, Pentti J.

julkaisussa: Journal of the Neurological Sciences, Vuosikerta 236, 2005, s. 17-24.

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

TY - JOUR

T1 - Chromosome 21 BACE2 haplotype associates with Alzheimer's disease

T2 - a two-stage study

AU - Myllykangas, Liisa

AU - Wavrant-De Vrieze, Fabienne

AU - Polvikoski, Tuomo

AU - Notkola, Irma-Leena

AU - Sulkava, Raimo

AU - Niinistö, Leena

AU - Edland, Steven D

AU - Arepalli, Sampath

AU - Adighibe, Omanma

AU - Compton, Danielle

AU - Hardy, John

AU - Haltia, Matti

AU - Tienari, Pentti J

PY - 2005

Y1 - 2005

N2 - 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. (c) 2005 Elsevier B.V. All rights reserved.

AB - 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. (c) 2005 Elsevier B.V. All rights reserved.

U2 - 10.1016/j.jns.2005.04.008

DO - 10.1016/j.jns.2005.04.008

M3 - Article

VL - 236

SP - 17

EP - 24

JO - Journal of the Neurological Sciences

JF - Journal of the Neurological Sciences

SN - 0022-510X

ER -