Integrated Quantile RAnk Test (iQRAT) for gene-level associations

TL;DR

This paper introduces the integrated quantile rank test (iQRAT), a novel gene-level association testing method that captures complex, heterogeneous genetic associations more effectively than traditional mean or variance-based tests.

Contribution

The paper proposes a new family of gene-level association tests using quantile rank score processes, improving detection of complex genetic associations and providing distribution-free, computationally efficient analysis.

Findings

iQRAT performs well in simulations for heterogeneous associations

iQRAT offers insights into risk stratification

Application to Metabochip data identifies novel associations

Abstract

Gene-based testing is a commonly employed strategy in many genetic association studies. Gene-trait associations can be complex due to underlying population heterogeneity, gene-environment interactions, and various other reasons. Existing gene-based tests, such as Burden and Sequence Kernel Association Tests (SKAT), are based on detecting differences in a single summary statistic, such as the mean or the variance, and may miss or underestimate higher-order associations that could be scientifically interesting. In this paper, we propose a new family of gene-level association tests which integrate quantile rank score processes to better accommodate complex associations. The resulting test statistics have multiple advantages: (1) they are almost as efficient as the best existing tests when the associations are homogeneous across quantile levels, and have improved efficiency for complex and heterogeneous associations, (2) they provide useful insights on risk stratification, (3) the test statistics are distribution-free, and could hence accommodate a wide range of underlying distributions, and (4) they are computationally efficient. We established the asymptotic properties of the proposed tests under the null and alternative hypothesis and conducted large scale simulation studies to investigate their finite sample performance. We applied the proposed tests to the Metabochip data to identify genetic associations with lipid traits and compared the results with those of the Burden and SKAT tests.