J Alzheimers Dis. 2014;41(4):1063-71.

Ordered subset analysis of copy number variation association with age at onset of Alzheimer’s disease.

Szigeti K, et al.

Department of Neurology, University at Buffalo, SUNY, Buffalo, NY, USA.

 

Abstract

Genetic heterogeneity is a common problem for genome-wide association studies of complex human diseases. Ordered-subset analysis (OSA) reduces genetic heterogeneity and optimizes the use of phenotypic information, thus improving power under some disease models. We hypothesized that in a genetically heterogeneous disorder such as Alzheimer’s disease (AD), utilizing OSA by age at onset (AAO) of AD may increase the power to detect relevant loci. Using this approach, 8 loci were detected, including the chr15 : 30,44 region harboring CHRFAM7A. The association was replicated in the NIA-LOAD Familial Study dataset. CHRFAM7A is a dominant negative regulator of CHRNA7 function, the receptor that facilitates amyloid-β1-42 internalization through endocytosis and has been implicated in AD. OSA, using AAO as a quantitative trait, optimized power and detected replicable signals suggesting that AD is genetically heterogeneous between AAO subsets.

KEYWORDS: Age at onset; Alzheimer’s disease; copy number variation

PMID: 24787912

 

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