Abstract
With the advance of next-generation sequencing technology, the rare variants join the common ones in explaining more proportions of heritability. The coexistence of variants of common with rare, causal with neutral and deleterious with protective is a norm and should be appropriately addressed. Some existing methods suffer from low power when one or more forms of coexistence present, impeding their applications in practice. In this paper, for case–parent trios, pseudocontrols are constructed using the nontransmitted alleles of the parents. The Kullback–Leibler divergence is utilized to measure the difference between the distributions of variants in a genetic region for the affected children and pseudocontrols, and two nonparametric test statistics KLTT and cKLTT are proposed. Extensive simulations show that they are robust to the opposite directions of the causal variants and the amount of neutral variants, and have superiority over the existing methods when both rare and common variants are involved. Furthermore, their efficiency is demonstrated in the application to the data from Framingham Heart Study.
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Acknowledgements
We thank two anonymous reviewers for their constructive comments and suggestions that improve the presentation of the manuscript greatly. We thank the FHS participants and acknowledge support from N01-HC25195. This work was supported in part by National Natural Science Foundation of China (11571082, 11171075), National Basic Research Program of China (2012CB316505) and the Scientific Research Foundation of Fudan University.
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Wang, C., Sun, L., Zheng, H. et al. Detecting multiple variants associated with disease based on sequencing data of case–parent trios. J Hum Genet 61, 851–860 (2016). https://doi.org/10.1038/jhg.2016.63
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DOI: https://doi.org/10.1038/jhg.2016.63
