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Meta-Analysis
. 2023 Oct 3;29(10):1622-1632.
doi: 10.1093/ibd/izad089.

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

Michelle Khrom  1 , Dalin Li  1 , Takeo Naito  1 , Ho-Su Lee  2 , Gregory J Botwin  1 , Alka A Potdar  1 , Gabrielle Boucher  3 ; NIDDK Inflammatory Bowel Disease Genetics Consortium; International Inflammatory Bowel Disease Genetics Consortium; Shaohong Yang  1 , Emebet Mengesha  1 , Shishir Dube  1 , Kyuyoung Song  2 , Dermot P B McGovern  1 , Talin Haritunians  1
Affiliations
Meta-Analysis

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

Michelle Khrom et al. Inflamm Bowel Dis. .

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.

Keywords: genetics; inflammatory bowel disease; sex dimorphic.

Plain language summary

Sex-dimorphic meta-analyses of sex-stratified case-control (n = 73 704) regression identified 3 novel inflammatory bowel disease loci reaching genome-wide significance and highlighted chromosome 2 and major histocompatibility complex variants exhibiting sex-specific association. In addition, a novel chromosome X Crohn’s disease susceptibility locus was identified.

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Conflict of interest statement

Cedars-Sinai has financial interests in Prometheus Biosciences, Inc, a company that has access to the data and specimens in Cedars-Sinai’s MIRIAD Biobank (including some of the genetic data used in this study) and seeks to develop commercial products. D.P.B.M. owns stock in Prometheus Biosciences Inc. A.A.P., D.L., and D.P.B.M. are consultants for Prometheus Biosciences, Inc. D.P.B.M. has served as a consultant for Gilead, Pfizer, Boehringer Ingelheim, Qu Biologics, Bridge Biotherapeutics, Takeda, and Palatin Technologies; and received grant support from Janssen. The other authors disclose no conflicts.

Figures

Graphical Abstract
Graphical Abstract
Figure 1.
Figure 1.
Schematic describing analysis workflow. *Single nucleotide polymorphism located outside the 1 Mb window of previously reported variants in an inflammatory bowel disease–associated genomic region and r2 < 0.2 with previously reported single nucleotide polymorphism.15 **P ≥ .05 in the opposite sex in sex-specific meta-analyses. #Variants 5 × 10-8 < P2-df sex-dimorphic < 5 × 10-7 evaluated for sex-specific association are listed in Supplementary Table 3.
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