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

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-?1-42 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.

SUBMITTER: Szigeti K 

PROVIDER: S-EPMC4866488 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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

Szigeti Kinga K   Kellermayer Blanka B   Lentini Jenna M JM   Trummer Brian B   Lal Deepika D   Doody Rachelle S RS   Yan Li L   Liu Song S   Ma Changxing C  

Journal of Alzheimer's disease : JAD 20140101 4

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  ...[more]

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