Kullback–Leibler Distance Methods for Detecting Disease Association with Rare Variants from Sequencing Data

Because next generation sequencing technology that can rapidly genotype most genetic variations genome, there is considerable interest in investigating the effects of rare variants on complex diseases. In this paper, we propose four Kullback–Leibler distance‐based Tests (KLTs) for detecting genotypic differences between cases and controls. There are several features that set the proposed tests apart from existing ones. First, by explicitly considering and comparing the distributions of genotypes, existence of variants with opposite directional effects does not compromise the power of KLTs. Second, it is not necessary to set a threshold for rare variants as the KL definition makes it reasonable to consider rare and common variants together without worrying about the contribution from one type overshadowing the other. Third, KLTs are robust to null variants thanks to a built‐in noise fighting mechanism. Finally, correlation among variants is taken into account implicitly so the KLTs work well regardless of the underlying LD structure. Through extensive simulations, we demonstrated good performance of KLTs compared to the sum of squared score test (SSU) and optimal sequence kernel association test (SKAT‐O). Moreover, application to the Dallas Heart Study data illustrates the feasibility and performance of KLTs in a realistic setting.