Fisher's method of combining dependent statistics using generalizations of the gamma distribution with applications to genetic pleiotropic associations

Abstract

A classical approach to combine independent test statistics is Fisher's combination of $p$-values, which follows the $\chi ^2$ distribution. When the test statistics are dependent, the gamma distribution (GD) is commonly used for the Fisher's combination test (FCT). We propose to use two generalizations of the GD: the generalized and the exponentiated GDs. We study some properties of mis-using the GD for the FCT to combine dependent statistics when one of the two proposed distributions are true. Our results show that both generalizations have better control of type I error rates than the GD, which tends to have inflated type I error rates at more extreme tails. In practice, common model selection criteria (e.g. Akaike information criterion/Bayesian information criterion) can be used to help select a better distribution to use for the FCT. A simple strategy of the two generalizations of the GD in genome-wide association studies is discussed. Applications of the results to genetic pleiotrophic associations are described, where multiple traits are tested for association with a single marker.