PERMORY: an LD-exploiting permutation test algorithm for powerful genome-wide association testing

Motivation: In genome-wide association studies (GWAS) examining hundreds of thousands of genetic markers, the potentially high number of false positive findings requires statistical correction for multiple testing. Permutation tests are considered the gold standard for multiple testing correction in GWAS, because they simultaneously provide unbiased type I error control and high power. At the same time, they demand heavy computational effort, especially with large-scale datasets of modern GWAS. In recent years, the computational problem has been circumvented by using approximations to permutation tests, which, however, may be biased. Results: We have tackled the original computational problem of permutation testing in GWAS and herein present a permutation test algorithm one or more orders of magnitude faster than existing implementations, which enables efficient permutation testing on a genome-wide scale. Our algorithm does not rely on any kind of approximation and hence produces unbiased results identical to a standard permutation test. A noteworthy feature of our algorithm is a particularly effective performance when analyzing high-density marker sets.