Ordered subset analysis of copy number variation association with age at onset of Alzheimer's disease.
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.
Department of Neurology, University at Buffalo, SUNY, Buffalo, NY, USA.
Kinga
K
Szigeti
Department of Neurology, University at Buffalo, SUNY, Buffalo, NY, USA.
Blanka
B
Kellermayer
Department of Neurology, University at Buffalo, SUNY, Buffalo, NY, USA.
Jenna M
JM
Lentini
Department of Neurology, University at Buffalo, SUNY, Buffalo, NY, USA.
Brian
B
Trummer
Department of Neurology, University at Buffalo, SUNY, Buffalo, NY, USA.
Deepika
D
Lal
Alzheimer's Disease and Memory Disorders Center, Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
Rachelle S
RS
Doody
Department of Bioinformatics, University at Buffalo, SUNY, Buffalo, NY, USA.
Li
L
Yan
Roswell Park Cancer Institute, Buffalo, NY, USA.
Song
S
Liu
Department of Bioinformatics, University at Buffalo, SUNY, Buffalo, NY, USA.
Changxing
C
Ma
D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D001921:Brain / Q000378:metabolism; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D066264:Datasets as Topic; D005260:Female; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics*
D001057:Apolipoproteins E; C579167:Chrna7 protein, human; D064569:alpha7 Nicotinic Acetylcholine Receptor
Age at onset; Alzheimer's disease; copy number variation