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Article
Functional Analysis of Variance for Association Studies
PLOS ONE (2014)
  • Olga A. Vsevolozhskaya, Michigan State University
  • Dmitri V. Zaykin
  • Mark C. Greenwood, Montana State University
  • Changshuai Wei, Michigan State University
  • Qing Lu, Michigan State University
Abstract

While progress has been made in identifying common genetic variants associated with human diseases, for most of common complex diseases, the identified genetic variants only account for a small proportion of heritability. Challenges remain in finding additional unknown genetic variants predisposing to complex diseases. With the advance in next-generation sequencing technologies, sequencing studies have become commonplace in genetic research. The ongoing exome-sequencing and whole-genome-sequencing studies generate a massive amount of sequencing variants and allow researchers to comprehensively investigate their role in human diseases. The discovery of new disease-associated variants can be enhanced by utilizing powerful and computationally efficient statistical methods. In this paper, we propose a functional analysis of variance (FANOVA) method for testing an association of sequence variants in a genomic region with a qualitative trait. The FANOVA has a number of advantages: (1) it tests for a joint effect of gene variants, including both common and rare; (2) it fully utilizes linkage disequilibrium and genetic position information; and (3) allows for either protective or risk-increasing causal variants. Through simulations, we show that FANOVA outperform two popularly used methods – SKAT and a previously proposed method based on functional linear models (FLM), – especially if a sample size of a study is small and/or sequence variants have low to moderate effects. We conduct an empirical study by applying three methods (FANOVA, SKAT and FLM) to sequencing data from Dallas Heart Study. While SKAT and FLM respectively detected ANGPTL 4 and ANGPTL 3 associated with obesity, FANOVA was able to identify both genes associated with obesity.

Keywords
  • Genetics,
  • Disease,
  • Variant genotypes,
  • Permutation,
  • Simulation,
  • Functional analysis,
  • Test statistics,
  • Obesity
Disciplines
Publication Date
September 22, 2014
Publisher Statement
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Citation Information
Olga A. Vsevolozhskaya, Dmitri V. Zaykin, Mark C. Greenwood, Changshuai Wei, et al.. "Functional Analysis of Variance for Association Studies" PLOS ONE Vol. 9 Iss. 9 (2014)
Available at: http://works.bepress.com/vsevolozhskaya/2/