TY - JOUR T1 - Accounting for eXentricities: Analysis of the X chromosome in GWAS reveals X-linked genes implicated in autoimmune diseases JF - bioRxiv DO - 10.1101/009464 SP - 009464 AU - Diana Chang AU - Feng Gao AU - Li Ma AU - Aaron J. Sams AU - Andrea Slavney AU - Yedael Y. Waldman AU - Paul Billing-Ross AU - Aviv Madar AU - Richard Spritz AU - Alon Keinan Y1 - 2014/01/01 UR - http://biorxiv.org/content/early/2014/09/21/009464.abstract N2 - Many complex human diseases are highly sexually dimorphic, which suggests a potential contribution of the X chromosome. However, the X chromosome has been neglected 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 diseases (AID). We associated several X-linked genes with disease risk, among which 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. Additionally, we found that the centromere protein CENPI is associated with three different AID; replicated a previously investigated association of FOXP3, which regulates genes involved in T-cell function, in vitiligo; and 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, display differential gene expression between males and females, and participate in major immune pathways. Combined, the results demonstrate the importance of the X chromosome in autoimmunity, reveal the potential of XWAS, even based on existing data, and provide the tools and incentive to appropriately include the X chromosome in future studies. ER -