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Genet Epidemiol. 2014 Jul;38(5):447-56. doi: 10.1002/gepi.21813. Epub 2014 May 21.

Kernel-machine testing coupled with a rank-truncation method for genetic pathway analysis.

Author information

1
Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

Abstract

Traditional genome-wide association studies (GWASs) usually focus on single-marker analysis, which only accesses marginal effects. Pathway analysis, on the other hand, considers biological pathway gene marker hierarchical structure and therefore provides additional insights into the genetic architecture underlining complex diseases. Recently, a number of methods for pathway analysis have been proposed to assess the significance of a biological pathway from a collection of single-nucleotide polymorphisms. In this study, we propose a novel approach for pathway analysis that assesses the effects of genes using the sequence kernel association test and the effects of pathways using an extended adaptive rank truncated product statistic. It has been increasingly recognized that complex diseases are caused by both common and rare variants. We propose a new weighting scheme for genetic variants across the whole allelic frequency spectrum to be analyzed together without any form of frequency cutoff for defining rare variants. The proposed approach is flexible. It is applicable to both binary and continuous traits, and incorporating covariates is easy. Furthermore, it can be readily applied to GWAS data, exome-sequencing data, and deep resequencing data. We evaluate the new approach on data simulated under comprehensive scenarios and show that it has the highest power in most of the scenarios while maintaining the correct type I error rate. We also apply our proposed methodology to data from a study of the association between bipolar disorder and candidate pathways from Wellcome Trust Case Control Consortium (WTCCC) to show its utility.

KEYWORDS:

common variants; pathway analysis; rare variants; sequence kernel association test; truncation

PMID:
24849109
PMCID:
PMC4073214
DOI:
10.1002/gepi.21813
[Indexed for MEDLINE]
Free PMC Article
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