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 < 5 × 10-8) at loci not previously reported in large-scale IBD genetic studies, including at chr9q22, CARMIL1, and UBASH3A. We identified variants in known IBD loci, including in chr2p15 and within the major histocompatibility complex on chr6, exhibiting sex-specific patterns of association (P < 5 × 10-7 in one sex only). We identified 3 chrX associations with IBD, including a novel Crohn’s disease susceptibility locus at Xp22. Conclusions These analyses identified novel IBD loci, in addition to characterizing sex-specific patterns of associations underlying sex-dimorphic associations. By elucidating the role of sex in IBD genetics, our study will help enhance our understanding of the differences between the sexes in IBD biology and underscores a need to move beyond conventional sex-combined analyses to appreciate the genetic architecture of IBD more comprehensively.