FARVATX: Family-Based Rare Variant Association Test for X-Linked Genes.
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.
Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Korea.
Sungkyoung
S
Choi
Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Korea.
Sungyoung
S
Lee
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Dandi
D
Qiao
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
Megan
M
Hardin
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
Michael H
MH
Cho
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
Edwin K
EK
Silverman
Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Korea.|Department of Statistics, Seoul National University, Seoul, Korea.
Taesung
T
Park
Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Korea.|Department of Public Health Science, Seoul National University, Seoul, Korea.|Institute of Health and Environment, Seoul National University, Seoul, Korea.
Sungho
S
Won
D000483:Alleles; D041321:Chromosomes, Human, X; D005260:Female; D050172:Genes, X-Linked; D014644:Genetic Variation; D006801:Humans; D008957:Models, Genetic; D010375:Pedigree; D010641:Phenotype; D049951:X Chromosome Inactivation
X chromosome; X chromosome inactivation; extended families; genetic association analysis; rare variants