Association Testing Strategy for Data from Dense Marker Panels

Authors

Donghyung Lee, Virginia Commonwealth UniversityFollow
Silviu-Alin Bacanu, Virginia Commonwealth University

Document Type

Article

Original Publication Date

2013

Journal/Book/Conference Title

PLOS ONE

Volume

8

DOI of Original Publication

10.1371/journal.pone.0080540

Comments

Originally Published at http://dx.doi.org/10.1371/journal.pone.0080540

Date of Submission

November 2014

Abstract

Genome wide association studies have been usually analyzed in a univariate manner. The commonly used univariate tests have one degree of freedom and assume an additive mode of inheritance. The experiment-wise significance of these univariate statistics is obtained by adjusting for multiple testing. Next generation sequencing studies, which assay 10-20 million variants, are beginning to come online. For these studies, the strategy of additive univariate testing and multiple testing adjustment is likely to result in a loss of power due to (1) the substantial multiple testing burden and (2) the possibility of a non-additive causal mode of inheritance. To reduce the power loss we propose: a new method (1) to summarize in a single statistic the strength of the association signals coming from all not-very-rare variants in a linkage disequilibrium block and (2) to incorporate, in any linkage disequilibrium block statistic, the strength of the association signals under multiple modes of inheritance. The proposed linkage disequilibrium block test consists of the sum of squares of nominally significant univariate statistics. We compare the performance of this method to the performance of existing linkage disequilibrium block/gene-based methods. Simulations show that (1) extending methods to combine testing for multiple modes of inheritance leads to substantial power gains, especially for a recessive mode of inheritance, and (2) the proposed method has a good overall performance. Based on simulation results, we provide practical advice on choosing suitable methods for applied analyses.

Rights

Copyright: © 2013 Lee, Bacanu. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Is Part Of

VCU Psychiatry Publications