A statistical measure for the skewness of X chromosome inactivation for quantitative traits and its application to the MCTFR data

Abstract

Background: X chromosome inactivation (XCI) is that one of two chromosomes in mammalian females is silenced during early development of embryos. There has been a statistical measure for the degree of the skewness of XCI for qualitative traits. However, no method is available for such task at quantitative trait loci. Results: In this article, we extend the existing statistical measure for the skewness of XCI for qualitative traits, and the likelihood ratio, Fieller’s and delta methods for constructing the corresponding confidence intervals, and make them accommodate quantitative traits. The proposed measure is a ratio of two linear regression coefficients when association exists. Noting that XCI may cause variance heterogeneity of the traits across different genotypes in females, we obtain the point estimate and confidence intervals of the measure by incorporating such information. The hypothesis testing of the proposed methods is also investigated. We conduct extensive simulation studies to assess the performance of the proposed methods. Simulation results demonstrate that the median of the point estimates of the measure is very close to the pre-specified true value. The likelihood ratio and Fieller’s methods control the size well, and have the similar test power and accurate coverage probability, which perform better than the delta method. So far, we are not aware of any association study for the X-chromosomal loci in the Minnesota Center for Twin and Family Research data. So, we apply our proposed methods to these data for their practical use and find that only the rs792959 locus, which is simultaneously associated with the illicit drug composite score and behavioral disinhibition composite score, may undergo XCI skewing. However, this needs to be confirmed by molecular genetics. Conclusions: We recommend the Fieller’s method in practical use because it is a non-iterative procedure and has the similar performance to the likelihood ratio method.