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

J Alzheimers Dis. 2014;41(4):1063-71. doi: 10.3233/JAD-132693.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • Apolipoproteins E / genetics
  • Brain / metabolism
  • Cohort Studies
  • DNA Copy Number Variations / genetics*
  • Datasets as Topic
  • Female
  • Gene Expression Profiling
  • Genetic Association Studies
  • Genetic Heterogeneity
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • alpha7 Nicotinic Acetylcholine Receptor / genetics*


  • Apolipoproteins E
  • Chrna7 protein, human
  • alpha7 Nicotinic Acetylcholine Receptor