FARVATX: Family‐Based Rare Variant Association Test for X‐Linked Genes

Abstract

Although the X chromosome has many genes that are functionally related to human diseases, the complicated biological properties of the X chromosome have prevented efficient genetic association analyses, and only a few significantly associated X-linked variants have been reported for complex traits. For instance, dosage compensation of X-linked genes is often achieved via the inactivation of one allele in each X-linked variant in females; however, some X-linked variants can escape this X chromosome inactivation. Efficient genetic analyses cannot be conducted without prior knowledge about the gene expression process of X-linked variants, and misspecified information can lead to power loss. In this report, we propose new statistical methods for rare X-linked variant genetic association analysis of dichotomous phenotypes with family-based samples. The proposed methods are computationally efficient and can complete X-linked analyses within a few hours. Simulation studies demonstrate the statistical efficiency of the proposed methods, which were then applied to rare-variant association analysis of the X chromosome in chronic obstructive pulmonary disease (COPD). Some promising significant X-linked genes were identified, illustrating the practical importance of the proposed methods.

X Chromosome Associations with Chronic Obstructive Pulmonary Disease and Related Phenotypes: An X Chromosome-wide Association Study

“…Escape from XCI results in sex biases in gene expression and has implications for the role of the X chromosome in human diseases, including intellectual disability, autoimmune disease, and cancer [34,35,45,46,48,51]. It has been suggested that escape from XCI is a mechanism for respiratory disease pathology in COPD and that escape from XCI influences lung tissue transcription [52]. POU3F4 was the only suggested variant in the current analysis that is a transcription factor.…”

WISARD: workbench for integrated superfast association studies for related datasets

“…For gene-level association analysis, WISARD supports six types of gene mapping file format: refFlat format, two interval formats and three direct mapping format while other toolsets support only one or two formats. In addition, WISARD has more functions for statistical analyses such as X-chromosome gene-level association analysis with the family-based dataset, FARVATx [ 30 ], and allows multi-thread analyses except few analyses such as PCA analysis and heritability with ‘--thread’ option.…”

“…In particular, most of gene-level tests were limited to population-based samples, and few approaches available for family-based samples. PEDCMC [ 27 ], FARVAT [ 28 ], mFARVAT [ 29 ], and FARVATx [ 30 ] are implemented in WISARD. Furthermore, we provided new statistics, family-based VT and family-based SKAT-o.…”

X chromosome associations with chronic obstructive pulmonary disease and related phenotypes: an X chromosome-wide association study

“…Escape from XCI results in sex biases in gene expression and has implications for the role of the X chromosome in human diseases, including intellectual disability, autoimmune disease, and cancer [ 34 , 35 , 45 , 46 , 48 , 51 ]. It has been suggested that escape from XCI is a mechanism for respiratory disease pathology in COPD and that escape from XCI influences lung tissue transcription [ 52 ]. POU3F4 was the only suggested variant in the current analysis that is a transcription factor.…”