Detecting association of rare variants by testing an optimally weighted combination of variants for quantitative traits in general families

Abstract

Although next-generation sequencing technology allows sequencing the whole genome of large groups of individuals, the development of powerful statistical methods for rare variant association studies is still underway. Even though many statistical methods have been developed for mapping rare variants, most of these methods are for unrelated individuals only, whereas family data have been shown to improve power to detect rare variants. The majority of the existing methods for unrelated individuals is essentially testing the effect of a weighted combination of variants with different weighting schemes. The performance of these methods depends on the weights being used. Recently, researchers proposed a test for Testing the effect of an Optimally Weighted combination of variants (TOW) for unrelated individuals. In this article, we extend our previously developed TOW for unrelated individuals to family-based data and propose a novel test for Testing the effect of an Optimally Weighted combination of variants for Family-based designs (TOW-F). The optimal weights are analytically derived. The results of extensive simulation studies show that TOW-F is robust to population stratification in a wide range of population structures, is robust to the direction and magnitude of the effects of causal variants, and is relatively robust to the percentage of neutral variants.

Keywords: Rare variants; association studies; general families; population stratification; quantitative traits.

Figure 1

The pedigree structure used in the simulation studies.

Figure 2

Power comparison as a function of the heritability of analyzed causal variants. The colors red, blue, black, green, and purple represent powers of TOW-F, WS-FBAT, Tmax, AW-FBAT, and TOW-F1 respectively. In this scenario, we assume that the percentage of neutral variants is 90% and all causal variants are risk variants. “nuclear families” means that this set of simulations is based on 800 families with 2 children in each family. “pedigrees” means that this set of simulations is based on 200 pedigrees given in figure 1.

Figure 3

Power comparison as a function of the percentage of neutral variants. The colors red, blue, black, green, and purple represent powers of TOW-F, WS-FBAT, Tmax, AW-FBAT, and TOW-F1 respectively. In this scenario, we assume that the heritability of analyzed causal variants is 0.02 and all causal variants are risk variants. “nuclear families” means that this set of simulations is based on 800 families with 2 children in each family. “pedigrees” means that this set of simulations is based on 200 pedigrees given in figure 1.

Figure 4

Power comparison as a function of the percentage of protective variants. The colors red, blue, black, green, and purple represent powers of TOW-F, WS-FBAT, Tmax, AW-FBAT, and TOW-F1 respectively. In this scenario, we assume that the heritability of analyzed causal variants is 0.02 and the percentage of neutral variants is 90%. “nuclear families” means that this set of simulations is based on 800 families with 2 children in each family. “pedigrees” means that this set of simulations is based on 200 pedigrees given in figure 1.