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Robust Rare-Variant Association Tests for Quantitative Traits in General Pedigrees

Author

Listed:
  • Yunxuan Jiang

    (Emory University)

  • Karen N. Conneely

    (Emory University)

  • Michael P. Epstein

    (Emory University)

Abstract

Next-generation sequencing technology has propelled the development of statistical methods to identify rare polygenetic variation associated with complex traits. The majority of these statistical methods are designed for case–control or population-based studies, with few methods that are applicable to family-based studies. Moreover, existing methods for family-based studies mainly focus on trios or nuclear families; there are far fewer existing methods available for analyzing larger pedigrees of arbitrary size and structure. To fill this gap, we propose a method for rare-variant analysis in large pedigree studies that can utilize information from all available relatives. Our approach is based on a kernel machine regression (KMR) framework, which has the advantages of high power, as well as fast and easy calculation of p-values using the asymptotic distribution. Our method is also robust to population stratification due to integration of a QTDT framework (Abecasis et al., Eur J Hum Genet 8(7):545–551, 2000b) with the KMR framework. In our method, we first calculate the expected genotype (between-family component) of a non-founder using all founders’ information and then calculate the deviates (within-family component) of observed genotype from the expectation, where the deviates are robust to population stratification by design. The test statistic, which is constructed using within-family component, is thus robust to population stratification. We illustrate and evaluate our method using simulated data and sequence data from Genetic Analysis Workshop 18.

Suggested Citation

  • Yunxuan Jiang & Karen N. Conneely & Michael P. Epstein, 2018. "Robust Rare-Variant Association Tests for Quantitative Traits in General Pedigrees," Statistics in Biosciences, Springer;International Chinese Statistical Association, vol. 10(3), pages 491-505, December.
    • Handle: RePEc:spr:stabio:v:10:y:2018:i:3:d:10.1007_s12561-017-9197-9
    DOI: 10.1007/s12561-017-9197-9
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    References listed on IDEAS

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    1. Dawei Liu & Xihong Lin & Debashis Ghosh, 2007. "Semiparametric Regression of Multidimensional Genetic Pathway Data: Least-Squares Kernel Machines and Linear Mixed Models," Biometrics, The International Biometric Society, vol. 63(4), pages 1079-1088, December.
    2. Robert B. Davies, 1980. "The Distribution of a Linear Combination of χ2 Random Variables," Journal of the Royal Statistical Society Series C, Royal Statistical Society, vol. 29(3), pages 323-333, November.
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