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A robust test for X-chromosome genetic association accounting for X-chromosome inactivation and imprinting.

ABSTRACT: The X chromosome is known to play an important role in many sex-specific diseases. However, only a few single-nucleotide polymorphisms on the X chromosome have been found to be associated with diseases. Compared to the autosomes, conducting association tests on the X chromosome is more intractable due to the difference in the number of X chromosomes between females and males. On the other hand, X-chromosome inactivation takes place in female mammals, which is a phenomenon in which the expression of one copy of two X chromosomes in females is silenced in order to achieve the same gene expression level as that in males. In addition, imprinting effects may be related to certain diseases. Currently, there are some existing approaches taking X-chromosome inactivation into account when testing for associations on the X chromosome. However, none of them allows for imprinting effects. Therefore, in this paper, we propose a robust test, ZXCII, which accounts for both X-chromosome inactivation and imprinting effects without requiring specifying the genetic models in advance. Simulation studies are conducted in order to investigate the validity and performance of ZXCII under various scenarios of different parameter values. The simulation results show that ZXCII controls the type I error rate well when there is no association. Furthermore, with regards to power, ZXCII is robust in all of the situations considered and generally outperforms most of the existing methods in the presence of imprinting effects, especially under complete imprinting effects.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7132553 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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A robust test for X-chromosome genetic association accounting for X-chromosome inactivation and imprinting.

Zhang Yu Y Xu Si-Qi SQ Liu Wei W Fung Wing Kam WK Zhou Ji-Yuan JY

Genetics research 20200401

The X chromosome is known to play an important role in many sex-specific diseases. However, only a few single-nucleotide polymorphisms on the X chromosome have been found to be associated with diseases. Compared to the autosomes, conducting association tests on the X chromosome is more intractable due to the difference in the number of X chromosomes between females and males. On the other hand, X-chromosome inactivation takes place in female mammals, which is a phenomenon in which the expression ...[more]

PMID: 32234109

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Project description:Despite being assayed on commercialized DNA chips, the X chromosome is commonly excluded from genome-wide association studies (GWAS). One of the reasons is the complexity to analyze the data taking into account the X-chromosome inactivation (XCI) process in women and in particular the XCI process with a potentially skewed pattern. This is the case when investigating the role of X-linked genetic variants in the occurrence of anti-drug antibodies (ADAs) in patients with autoimmune diseases treated by biotherapies. In this context, we propose a novel test statistic for selecting loci of interest harbored by the X chromosome that are associated with time-to-event data taking into account skewed X-inactivation (XCI-S). The proposed statistic relies on a semi-parametric additive hazard model and is straightforward to implement. Results from the simulation study show that the test provides higher power gains than the score tests from the Cox model (under XCI process or its escape) and the Xu et al.'s XCI-S likelihood ratio test. We applied the test to the data from the real-world observational multicohort study set-up by the IMI-funded ABIRISK consortium for identifying X chromosome susceptibility loci for drug immunogenicity in patients with autoimmune diseases treated by biotherapies. The test allowed us to select two single nucleotide polymorphisms (SNPs) with high linkage disequilibrium (rs5991366 and rs5991394) located in the cytoband Xp22.2 that would have been overlooked by the Cox score tests and the Xu et al.'s XCI-S likelihood ratio test. Both SNPs showed a similar protective effect for drug immunogenicity without any occurrence of ADA positivity for the homozygous females and hemizygous males for the alternative allele. To our knowledge, this is the first study to investigate the association between X chromosome loci and the occurrence of anti-drug antibodies. We think that more X-Chromosome GWAS should be performed and that the test is well-suited for identifying X-Chromosome SNPs, while taking into account all patterns of the skewed X-Chromosome inactivation process.

Dataset Information

A robust test for X-chromosome genetic association accounting for X-chromosome inactivation and imprinting.

Publications

A robust test for X-chromosome genetic association accounting for X-chromosome inactivation and imprinting.

Similar Datasets

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