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Accounting for eXentricities: Analysis of the X Chromosome in GWAS Reveals X-Linked Genes Implicated in Autoimmune Diseases

Author

Listed:
  • Diana Chang
  • Feng Gao
  • Andrea Slavney
  • Li Ma
  • Yedael Y Waldman
  • Aaron J Sams
  • Paul Billing-Ross
  • Aviv Madar
  • Richard Spritz
  • Alon Keinan

Abstract

Many complex human diseases are highly sexually dimorphic, suggesting a potential contribution of the X chromosome to disease risk. However, the X chromosome has been neglected or incorrectly analyzed in most genome-wide association studies (GWAS). We present tailored analytical methods and software that facilitate X-wide association studies (XWAS), which we further applied to reanalyze data from 16 GWAS of different autoimmune and related diseases (AID). We associated several X-linked genes with disease risk, among which (1) ARHGEF6 is associated with Crohn's disease and replicated in a study of ulcerative colitis, another inflammatory bowel disease (IBD). Indeed, ARHGEF6 interacts with a gastric bacterium that has been implicated in IBD. (2) CENPI is associated with three different AID, which is compelling in light of known associations with AID of autosomal genes encoding centromere proteins, as well as established autosomal evidence of pleiotropy between autoimmune diseases. (3) We replicated a previous association of FOXP3, a transcription factor that regulates T-cell development and function, with vitiligo; and (4) we discovered that C1GALT1C1 exhibits sex-specific effect on disease risk in both IBDs. These and other X-linked genes that we associated with AID tend to be highly expressed in tissues related to immune response, participate in major immune pathways, and display differential gene expression between males and females. Combined, the results demonstrate the importance of the X chromosome in autoimmunity, reveal the potential of extensive XWAS, even based on existing data, and provide the tools and incentive to properly include the X chromosome in future studies.

Suggested Citation

  • Diana Chang & Feng Gao & Andrea Slavney & Li Ma & Yedael Y Waldman & Aaron J Sams & Paul Billing-Ross & Aviv Madar & Richard Spritz & Alon Keinan, 2014. "Accounting for eXentricities: Analysis of the X Chromosome in GWAS Reveals X-Linked Genes Implicated in Autoimmune Diseases," PLOS ONE, Public Library of Science, vol. 9(12), pages 1-31, December.
    • Handle: RePEc:plo:pone00:0113684
    DOI: 10.1371/journal.pone.0113684
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    References listed on IDEAS

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    1. Jing Gu & Rui-Kun Peng & Chun-Ling Guo & Meng Zhang & Jie Yang & Xiao Yan & Qian Zhou & Hongwei Li & Na Wang & Jinwei Zhu & Qin Ouyang, 2022. "Construction of a synthetic methodology-based library and its application in identifying a GIT/PIX protein–protein interaction inhibitor," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Hao, Meiling & Zhao, Xingqiu & Xu, Wei, 2020. "Competing risk modeling and testing for X-chromosome genetic association," Computational Statistics & Data Analysis, Elsevier, vol. 151(C).

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