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. 2015 Feb;23(2):229-37.
doi: 10.1038/ejhg.2014.43. Epub 2014 Mar 26.

Test of rare variant association based on affected sib-pairs

Qiuying Sha  1 , Shuanglin Zhang  1
Affiliations

Test of rare variant association based on affected sib-pairs

Qiuying Sha et al. Eur J Hum Genet. 2015 Feb.

Abstract

With the development of sequencing techniques, there is increasing interest to detect associations between rare variants and complex traits. Quite a few statistical methods to detect associations between rare variants and complex traits have been developed for unrelated individuals. Statistical methods for detecting rare variant associations under family-based designs have not received as much attention as methods for unrelated individuals. Recent studies show that rare disease variants will be enriched in family data and thus family-based designs may improve power to detect rare variant associations. In this article, we propose a novel test to test association between the optimally weighted combination of variants and trait of interests for affected sib-pairs. The optimal weights are analytically derived and can be calculated from sampled genotypes and phenotypes. Based on the optimal weights, the proposed method is robust to the directions of the effects of causal variants and is less affected by neutral variants than existing methods are. Our simulation results show that, in all the cases, the proposed method is substantially more powerful than existing methods based on unrelated individuals and existing methods based on affected sib-pairs.

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Figures

Figure 1
Figure 1
Power comparisons of four tests for power as a function of number of affected sib-pairs. TOW and WSS are based on 1000 unrelated cases and 1000 unrelated controls. For TOW-sib and SPWSS, the sample size is 2000, where number of unrelated controls is 1000 and number of unrelated cases plus twice of the number of affected sib-pairs is 1000. Total heritability is 0.03. pcau denotes the percentage of causal variants in rare variants; pp denotes the percentage of protective variants in causal variants. The power is evaluated at a significance level of 0.001.
Figure 2
Figure 2
Powers as a function of heritability. TOW and WSS are based on 1000 unrelated cases and 1000 unrelated controls. SPWSS is based on 1000 unrelated controls, 600 unrelated cases, and 200 affected sib-pairs. TOW-sib is based on 1000 unrelated controls and 500 affected sib-pairs. pcau denotes the percentage of causal variants in rare variants; pp denotes the percentage of protective variants in causal variants. The power is evaluated at a significance level of 0.001.
Figure 3
Figure 3
Powers as a function of percentage of protective variants. TOW and WSS are based on 1000 unrelated cases and 1000 unrelated controls. SPWSS is based on 1000 unrelated controls, 600 unrelated cases, and 200 affected sib-pairs. TOW-sib is based on 1000 unrelated controls and 500 affected sib-pairs. pcau denotes the percentage of causal variants in rare variants; herit denotes the total heritability. The power is evaluated at a significance level of 0.001.
Figure 4
Figure 4
Powers as a function of percentage of causal variants. TOW and WSS are based on 1000 unrelated cases and 1000 unrelated controls. SPWSS is based on 1000 unrelated controls, 600 unrelated cases, and 200 affected sib-pairs. TOW-sib is based on 1000 unrelated controls and 500 affected sib-pairs. pp denotes the percentage of protective variants in causal variants; herit denotes the total heritability. The power is evaluated at a significance level of 0.001.
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