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

Genet Epidemiol. 2016 Sep;40(6):475-85. doi: 10.1002/gepi.21979. Epub 2016 Jun 21.


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. Some promising significant X-linked genes were identified, illustrating the practical importance of the proposed methods.

Keywords: X chromosome; X chromosome inactivation; extended families; genetic association analysis; rare variants.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Chromosomes, Human, X
  • Female
  • Genes, X-Linked*
  • Genetic Variation
  • Humans
  • Models, Genetic*
  • Pedigree
  • Phenotype
  • X Chromosome Inactivation