F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea.
Inflamm Bowel Dis. 2023 Oct 3;29(10):1622-1632. doi: 10.1093/ibd/izad089.
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.
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.
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.
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.
性别是复杂疾病遗传学中经常被忽视的一个重要变量。在炎症性肠病 (IBD) 的自然病史、疾病并发症和发病年龄方面，男女之间存在差异。虽然关联研究已经确定了超过 230 个 IBD 位点，但很少有研究调查这些遗传关联背后的性别差异。
我们报告了通过对性别分层关联研究（34579 例 IBD 病例，39125 例对照）进行荟萃分析，首次对性别二态性关联进行了研究。此外，我们还进行了 chrX 特异性分析，考虑了 X 染色体失活（XCI）和 XCI 逃逸的模型。还比较了男女之间的人口统计学和临床特征。
我们发现，在克罗恩病的疾病部位和肛周并发症以及溃疡性结肠炎的疾病程度方面，男女之间存在显著差异。我们观察到了以前在大型 IBD 遗传研究中未报道的全基因组显著性别二态性关联（P<5×10-8），包括在 chr9q22、CARMIL1 和 UBASH3A 上。我们在已知的 IBD 位点发现了变体，包括 chr2p15 和 chr6 上的主要组织相容性复合体内，这些变体表现出性别特异性的关联模式（仅在一个性别中 P<5×10-7）。我们在 chrX 上发现了 3 个与 IBD 相关的关联，包括 Xp22 上一个新的克罗恩病易感性位点。
这些分析确定了新的 IBD 位点，此外还描述了性别二态性关联背后性别特异性关联的模式。通过阐明性别在 IBD 遗传学中的作用，我们的研究将有助于增强我们对 IBD 生物学中男女之间差异的理解，并强调需要超越传统的两性混合分析，以更全面地了解 IBD 的遗传结构。
