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

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.

[1]  D. Schaid,et al.  A review of kernel methods for genetic association studies , 2019, Genetic epidemiology.

[2]  M. Möller,et al.  The X chromosome and sex-specific effects in infectious disease susceptibility , 2019, Human Genomics.

[3]  W. Fung,et al.  A statistical measure for the skewness of X chromosome inactivation based on case-control design , 2019, BMC Bioinformatics.

[4]  W. Fung,et al.  A robust and powerful test for case–control genetic association study on X chromosome , 2018, Statistical methods in medical research.

[5]  J. Ginebra,et al.  A Bayesian test for Hardy–Weinberg equilibrium of biallelic X-chromosomal markers , 2017, Heredity.

[6]  Hon Keung Tony Ng,et al.  Detecting associated single-nucleotide polymorphisms on the X chromosome in case control genome-wide association studies , 2017, Statistical methods in medical research.

[7]  J. Witte,et al.  Testing Allele Transmission of an SNP Set Using a Family‐Based Generalized Genetic Random Field Method , 2016, Genetic epidemiology.

[8]  A. Keinan,et al.  XWAS: A Software Toolset for Genetic Data Analysis and Association Studies of the X Chromosome. , 2015, The Journal of heredity.

[9]  Jian Wang,et al.  X‐Chromosome Genetic Association Test Accounting for X‐Inactivation, Skewed X‐Inactivation, and Escape from X‐Inactivation , 2014, Genetic epidemiology.

[10]  Andreas Ziegler,et al.  How to Include Chromosome X in Your Genome‐Wide Association Study , 2014, Genetic epidemiology.

[11]  T. Manolio,et al.  eXclusion: toward integrating the X chromosome in genome-wide association analyses. , 2013, American journal of human genetics.

[12]  A. McLysaght,et al.  Mammalian X chromosome inactivation evolved as a dosage-compensation mechanism for dosage-sensitive genes on the X chromosome , 2012, Proceedings of the National Academy of Sciences.

[13]  Xihong Lin,et al.  Rare-variant association testing for sequencing data with the sequence kernel association test. , 2011, American journal of human genetics.

[14]  Andreas Ziegler,et al.  Association Tests for X-Chromosomal Markers – A Comparison of Different Test Statistics , 2011, Human Heredity.

[15]  D. Clayton,et al.  The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes , 2009, Nature Genetics.

[16]  D. Clayton,et al.  Sex chromosomes and genetic association studies , 2009, Genome Medicine.

[17]  Art B. Owen,et al.  Karl Pearson’s meta analysis revisited , 2009, 0911.3531.

[18]  J. Starmer,et al.  A new model for random X chromosome inactivation , 2009, Development.

[19]  Andreas Ziegler,et al.  Genome‐wide association studies: quality control and population‐based measures , 2009, Genetic epidemiology.

[20]  Yoav Gilad,et al.  Sex-specific genetic architecture of human disease , 2008, Nature Reviews Genetics.

[21]  Jeannie T. Lee,et al.  X chromosome dosage compensation: how mammals keep the balance. , 2008, Annual review of genetics.

[22]  D. Clayton,et al.  Testing for association on the X chromosome , 2008, Biostatistics.

[23]  J. Cheverud,et al.  Maternal Effects as the Cause of Parent-of-Origin Effects That Mimic Genomic Imprinting , 2008, Genetics.

[24]  Carolyn J. Brown,et al.  A skewed view of X chromosome inactivation. , 2008, The Journal of clinical investigation.

[25]  Gang Zheng,et al.  Testing association for markers on the X chromosome , 2007, Genetic epidemiology.

[26]  Alan Y. Chiang,et al.  Generalized Additive Models: An Introduction With R , 2007, Technometrics.

[27]  I. König,et al.  A Statistical Approach to Genetic Epidemiology: Concepts and Applications , 2006 .

[28]  S. Wood.  Generalized Additive Models: An Introduction with R , 2006 .

[29]  R. J. Mitchell,et al.  Effect of Turner's syndrome and X-linked imprinting on cognitive status: analysis based on pedigree data , 2005, Brain and Development.

[30]  Carolyn J. Brown,et al.  Silencing of the mammalian X chromosome. , 2005, Annual review of genomics and human genetics.

[31]  H. Willard,et al.  X-inactivation profile reveals extensive variability in X-linked gene expression in females , 2005, Nature.

[32]  C. Amos,et al.  Possible genomic imprinting of three human obesity-related genetic loci. , 2005, American journal of human genetics.

[33]  H W Deng,et al.  The power of the transmission disequilibrium test (TDT) with both case-parent and control-parent trios. , 2001, Genetical research.

[34]  J. Gilbert,et al.  Female with autistic disorder and monosomy X (Turner syndrome): parent-of-origin effect of the X chromosome. , 2000, American journal of medical genetics.

[35]  D. Skuse,et al.  Imprinting, the X-Chromosome, and the Male Brain: Explaining Sex Differences in the Liability to Autism , 2000, Pediatric Research.

[36]  R. Jirtle,et al.  Genomic imprinting: implications for human disease. , 1999, The American journal of pathology.

[37]  B. Migeon.  Non-random X chromosome inactivation in mammalian cells , 1998, Cytogenetic and Genome Research.

[38]  D. Walkup,et al.  Association of Random Variables, with Applications , 1967 .

[39]  M. Kendall.  Statistical Methods for Research Workers , 1937, Nature.