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This article is part of the supplement: Genetic Analysis Workshop 17: Unraveling Human Exome Data

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Does pathway analysis make it easier for common variants to tag rare ones?

Hae-Won Uh12*, Roula Tsonaka1 and Jeanine J Houwing-Duistermaat1

Author Affiliations

1 Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands

2 Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands

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BMC Proceedings 2011, 5(Suppl 9):S90  doi:10.1186/1753-6561-5-S9-S90

Published: 29 November 2011


Analyzing sequencing data is difficult because of the low frequency of rare variants, which may result in low power to detect associations. We consider pathway analysis to detect multiple common and rare variants jointly and to investigate whether analysis at the pathway level provides an alternative strategy for identifying susceptibility genes. Available pathway analysis methods for data from genome-wide association studies might not be efficient because these methods are designed to detect common variants. Here, we investigate the performance of several existing pathway analysis methods for sequencing data. In particular, we consider the global test, which does not consider linkage disequilibrium between the variants in a gene. We improve the performance of the global test by assigning larger weights to rare variants, as proposed in the weighted-sum approach. Our conclusion is that straightforward application of pathway analysis is not satisfactory; hence, when common and rare variants are jointly analyzed, larger weights should be assigned to rare variants.