Avoiding the high Bonferroni penalty in genome-wide association studies.
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.
Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO 63108, USA. ray.x.gao@gmail.com
Xiaoyi
X
Gao
Lewis C
LC
Becker
Diane M
DM
Becker
Joshua D
JD
Starmer
Michael A
MA
Province
D001699:Biometry / Q000379:methods; D003627:Data Interpretation, Statistical; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis / Q000706:statistics & numerical data; D020641:Polymorphism, Single Nucleotide