Supplementary Material for: Model-Based Multifactor Dimensionality Reduction for Rare Variant Association Analysis

Genome-wide association studies have revealed a vast amount of common loci associated to human complex diseases. Still, a large proportion of heritability remains unexplained. The extent to which rare genetic variants (RVs) are able to explain a relevant portion of the genetic heritability for complex traits leaves room for several debates and paves the way to the collection of RV databases and the development of novel analytic tools to analyze these. To date, several statistical methods have been proposed to uncover the association of RVs with complex diseases, but none of them is the clear winner in all possible scenarios of study design and assumed underlying disease model. The latter may involve differences in the distributions of effect sizes, proportions of causal variants, and ratios of protective to deleterious variants at distinct regions throughout the genome. Therefore, there is a need for robust scalable methods with acceptable overall performance in terms of power and type I error under various realistic scenarios. In this paper, we propose a novel RV association analysis strategy, which satisfies several of the desired properties that a RV analysis tool should exhibit.