X-chromosome genetic association test incorporating X-chromosome inactivation and imprinting effects.

Studies have shown that many complex diseases are sex-determined. When conducting genetic association studies on X-chromosome, there are two important epigenetic factors which should be considered simultaneously: X-chromosome inactivation and genomic imprinting. Currently, there have been several association tests accounting for the information on X-chromosome inactivation. However, these tests do not take the imprinting effects into account. In this paper, we propose a novel association test simultaneously incorporating X-chromosome inactivation and imprinting effects based on case-parent trios and control-parent trios for female offspring and case-control data for male offspring, denoted by MLRXCII. Extensive simulation studies are carried out to investigate the type I error rate and the test power of the proposed MLRXCII . Simulation results demonstrate that the proposed test controls the type I error rate well andis more powerful than the existing method when imprinting effects exist. The proposed MLRXCII test is valid and powerful in genetic association studies on X-chromosome for qualitative traits and thus is recommended in practice.

A statistical measure for the skewness of X chromosome inactivation based on case-control design.

BACKGROUND: Skewed X chromosome inactivation (XCI), which is a non-random process, is frequently observed in both healthy and affected females. Furthermore, skewed XCI has been reported to be related to many X-linked diseases. However, no statistical method is available in the literature to measure the degree of the skewness of XCI for case-control design. Therefore, it is necessary to develop methods for such a task. RESULTS: In this article, we first proposed a statistical measure for the degree of XCI skewing by using a case-control design, which is a ratio of two logistic regression coefficients after a simple reparameterization. Based on the point estimate of the ratio, we further developed three types of confidence intervals (the likelihood ratio, Fieller's and delta methods) to evaluate its variation. Simulation results demonstrated that the likelihood ratio method and the Fieller's method have more accurate coverage probability and more balanced tail errors than the delta method. We also applied these proposed methods to analyze the Graves' disease data for their practical use and found that rs3827440 probably undergoes a skewed XCI pattern with 68.7% of cells in heterozygous females having the risk allele T active, while the other 31.3% of cells keeping the normal allele C active. CONCLUSIONS: For practical application, we suggest using the Fieller's method in large samples due to the non-iterative computation procedure and using the LR method otherwise for its robustness despite its slightly heavy computational burden.

A robust and powerful test for case-control genetic association study on X chromosome.

Hundreds of genome-wide association studies were conducted to map the disease genes on autosomes in human beings. It is known that many complex diseases are sex-determined and X chromosome is expected to play an important role. However, only a few single-nucleotide polymorphisms on X chromosome were found to be significantly associated with the diseases under study. On the other hand, to balance the genetic effect between two sexes, X chromosome inactivation occurs in most of X-linked genes by silencing one copy of two X chromosomes in females and dosage compensation is achieved. A few association studies on X chromosome incorporated the information on dosage compensation. However, some of them require the assumption of Hardy-Weinberg equilibrium and some need to specify the underlying genetic model. Therefore, in this article, we propose a novel method for association by taking account of different dosage compensation patterns. The proposed test is a robust approach because it requires neither specifying the underlying genetic models nor the assumption of Hardy-Weinberg equilibrium. Further, the proposed method allows for different deviations from Hardy-Weinberg equilibrium between cases and controls. Simulation results demonstrate that our proposed method generally outperforms the existing methods in terms of controlling the size and the test power. Finally, we apply the proposed test to the meta-analysis of the Graves' disease data for its practical use.

Effect of the 2008 cold spell on preterm births in two subtropical cities of Guangdong Province, Southern China.

BACKGROUND: A few studies have reported that low temperatures were associated with an increased risk of preterm birth. However, the effect of extreme weather events, such as cold spell, on preterm birth has not been studied in China. OBJECTIVE: This study was conducted to evaluate the impact of the 2008 cold spell on preterm birth in two subtropical cities of Guangdong Province. METHODS: Data of daily preterm birth, air pollution and meteorological variables from 2006 to 2010 were collected in Dongguan and Shenzhen. A Poisson regression with a distributed lag nonlinear model was used to investigate the association between the 2008 cold spell and daily rate of preterm birth for each city. RESULTS: During the 2008 cold spell, total vaginal preterm births were increased by 22.44% and 21.25% in Dongguan and Shenzhen, respectively. The effect of the cold spell on preterm births lasted for more than 1 week, the lag0-6 days cumulative relative risk (RR) is 1.32 (95% CI: 1.10-1.58) and 1.40 (95% CI: 1.18-1.68) in Dongguan and Shenzhen, respectively. The effects were found to be more pronounced for the pregnant women with 34-36 gestation weeks, maternal age < 35 years group. CONCLUSION: This study demonstrates that cold spell could increase the risk of preterm births in Dongguan and Shenzhen, and the effect lasts for more than 1 week. Specific measures should be considered to protect the pregnant women, especially the vulnerable subgroups.