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A Multi-Marker Genetic Association Test Based on the Rasch Model Applied to Alzheimer’s Disease

Author

Listed:
  • Wenjia Wang
  • Jonas Mandel
  • Jan Bouaziz
  • Daniel Commenges
  • Serguei Nabirotchkine
  • Ilya Chumakov
  • Daniel Cohen
  • Mickaël Guedj
  • the Alzheimer’s Disease Neuroimaging Initiative

Abstract

Results from Genome-Wide Association Studies (GWAS) have shown that the genetic basis of complex traits often include many genetic variants with small to moderate effects whose identification remains a challenging problem. In this context multi-marker analysis at the gene and pathway level can complement traditional point-wise approaches that treat the genetic markers individually. In this paper we propose a novel statistical approach for multi-marker analysis based on the Rasch model. The method summarizes the categorical genotypes of SNPs by a generalized logistic function into a genetic score that can be used for association analysis. Through different sets of simulations, the false-positive rate and power of the proposed approach are compared to a set of existing methods, and shows good performances. The application of the Rasch model on Alzheimer’s Disease (AD) ADNI GWAS dataset also allows a coherent interpretation of the results. Our analysis supports the idea that APOE is a major susceptibility gene for AD. In the top genes selected by proposed method, several could be functionally linked to AD. In particular, a pathway analysis of these genes also highlights the metabolism of cholesterol, that is known to play a key role in AD pathogenesis. Interestingly, many of these top genes can be integrated in a hypothetic signalling network.

Suggested Citation

  • Wenjia Wang & Jonas Mandel & Jan Bouaziz & Daniel Commenges & Serguei Nabirotchkine & Ilya Chumakov & Daniel Cohen & Mickaël Guedj & the Alzheimer’s Disease Neuroimaging Initiative, 2015. "A Multi-Marker Genetic Association Test Based on the Rasch Model Applied to Alzheimer’s Disease," PLOS ONE, Public Library of Science, vol. 10(9), pages 1-19, September.
  • Handle: RePEc:plo:pone00:0138223
    DOI: 10.1371/journal.pone.0138223
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    References listed on IDEAS

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    1. Brendan Maher, 2008. "Personal genomes: The case of the missing heritability," Nature, Nature, vol. 456(7218), pages 18-21, November.
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