Sex-Dimorphic Analyses Identify Novel and Sex-Specific Genetic Associations in Inflammatory Bowel Disease

Abstract Background Sex is an integral variable often overlooked in complex disease genetics. Differences between sexes have been reported in natural history, disease complications, and age of onset in inflammatory bowel disease (IBD). While association studies have identified >230 IBD loci, there have been a limited number of studies investigating sex differences underlying these genetic associations. Methods We report the first investigation of sex-dimorphic associations via meta-analysis of a sex-stratified association study (34 579 IBD cases, 39 125 controls). In addition, we performed chromosome (chr) X–specific analyses, considering models of X inactivation (XCI) and XCI escape. Demographic and clinical characteristics were also compared between sexes. Results We identified significant differences between sexes for disease location and perianal complication in Crohn’s disease and disease extent in ulcerative colitis. We observed genome-wide-significant sex-dimorphic associations (P