Abstract
BackgroundX 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.ResultsIn 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.ConclusionsWe 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.
Highlights
X chromosome inactivation (XCI) is that one of two chromosomes in mammalian females is silenced during early development of embryos
In genome-wide association study (GWAS), many human diseases have been found to be associated with X-chromosomal genes, such as autoimmune diseases [1, 2], asthma [3], Duchenne muscular dystrophy [4, 5], adrenoleukodystrophy [6], Wiskott-Aldrich syndrome [7] and some cancers [8,9,10,11,12]
There are two copies of X chromosome in mammalian females, one of which is paternal and the other is maternal, while mammalian males have only one maternal X chromosome. To compensate for this X chromosome dosage difference between sexes, one of two chromosomes in females is silenced during the early development of embryos, which is called X chromosome inactivation (XCI) [14,15,16,17,18]
Summary
X chromosome inactivation (XCI) is that one of two chromosomes in mammalian females is silenced during early development of embryos. There are two copies of X chromosome in mammalian females, one of which is paternal and the other is maternal, while mammalian males have only one maternal X chromosome To compensate for this X chromosome dosage difference between sexes, one of two chromosomes in females is silenced during the early development of embryos, which is called X chromosome inactivation (XCI) [14,15,16,17,18]. Random XCI (XCI-R) is a process that either the paternal or the maternal allele at an X-chromosomal locus is randomly chosen to be silenced in all cells, which is common in most females [19]. Over 15% X-linked genes have been shown to escape from XCI (XCI-E) [24, 25]
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