title: Accounting for eXentricities: analysis of the X chromosome in GWAS reveals X-linked genes implicated in autoimmune diseases.
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.
authors.affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America; Program in Computational Biology and Medicine, Cornell University, Ithaca, New York, United States of America.
authors.forename: Diana
authors.initials: D
authors.lastname: Chang
authors.affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America; Graduate Field of Genetics, Genomics and Development, Cornell University, Ithaca, New York, United States of America.
authors.forename: Andrea
authors.initials: A
authors.lastname: Slavney
authors.affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America; Department of Animal and Avian Sciences, University of Maryland, College Park, Maryland, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America.
authors.forename: Yedael Y
authors.initials: YY
authors.lastname: Waldman
authors.affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Sams
authors.affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America; Graduate Field of Genetics, Genomics and Development, Cornell University, Ithaca, New York, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Billing-Ross
authors.affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America.
authors.forename: Aviv
authors.initials: A
authors.lastname: Madar
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Spritz
authors.affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America; Program in Computational Biology and Medicine, Cornell University, Ithaca, New York, United States of America; Graduate Field of Genetics, Genomics and Development, Cornell University, Ithaca, New York, United States of America.
authors.forename: Alon
authors.initials: A
authors.lastname: Keinan
mesh_terms: D041321:Chromosomes, Human, X / Q000235:genetics*; D003093:Colitis, Ulcerative / Q000235:genetics; D003424:Crohn Disease / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics; D012727:Sex Characteristics; D012984:Software
chemical_list: C576603:ARHGEF6 protein, human; C505369:C1GALT1C1 protein, human; C484297:CENPI protein, human; D004268:DNA-Binding Proteins; D018832:Molecular Chaperones; D064067:Rho Guanine Nucleotide Exchange Factors