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

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

Author information

  • 1Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Korea.
  • 2Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
  • 3Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
  • 4Department of Statistics, Seoul National University, Seoul, Korea.
  • 5Department of Public Health Science, Seoul National University, Seoul, Korea.
  • 6Institute of Health and Environment, Seoul National University, Seoul, Korea.


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.


X chromosome; X chromosome inactivation; extended families; genetic association analysis; rare variants

[Available on 2017-09-01]
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