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Comparative Study
. 2010 Jan;34(1):100-5.
doi: 10.1002/gepi.20430.

Avoiding the high Bonferroni penalty in genome-wide association studies

Xiaoyi Gao  1 , Lewis C Becker, Diane M Becker, Joshua D Starmer, Michael A Province
Affiliations
Comparative Study

Avoiding the high Bonferroni penalty in genome-wide association studies

Xiaoyi Gao et al. Genet Epidemiol. 2010 Jan.

Abstract

A major challenge in genome-wide association studies (GWASs) is to derive the multiple testing threshold when hypothesis tests are conducted using a large number of single nucleotide polymorphisms. Permutation tests are considered the gold standard in multiple testing adjustment in genetic association studies. However, it is computationally intensive, especially for GWASs, and can be impractical if a large number of random shuffles are used to ensure accuracy. Many researchers have developed approximation algorithms to relieve the computing burden imposed by permutation. One particularly attractive alternative to permutation is to calculate the effective number of independent tests, M(eff), which has been shown to be promising in genetic association studies. In this study, we compare recently developed M(eff) methods and validate them by the permutation test with 10,000 random shuffles using two real GWAS data sets: an Illumina 1M BeadChip and an Affymetrix GeneChip Human Mapping 500K Array Set. Our results show that the simpleM method produces the best approximation of the permutation threshold, and it does so in the shortest amount of time. We also show that M(eff) is indeed valid on a genome-wide scale in these data sets based on statistical theory and significance tests. The significance thresholds derived can provide practical guidelines for other studies using similar population samples and genotyping platforms.

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Figures

Figure 1
Figure 1
Quantile-Quantile plot for minimum p-values using the Illumina 1M data.
Figure 2
Figure 2
Quantile-Quantile plot for minimum p-values using the Affymetrix 500K data.
See this image and copyright information in PMC

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