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. 2023;55(2):2281658.
doi: 10.1080/07853890.2023.2281658. Epub 2023 Nov 21.

Integrated analysis of Mendelian Randomization and Bayesian colocalization reveals bidirectional causal association between inflammatory bowel disease and psoriasis

Yangke Cai  1 , Siyuan Xie  1 , Xuan Jia  1 , Delong Chen  2 , Dehao Wu  3 , Wenwen Bao  1 , Jianting Cai  1 , Jianshan Mao  1 , Jun Ye  1
Affiliations

Integrated analysis of Mendelian Randomization and Bayesian colocalization reveals bidirectional causal association between inflammatory bowel disease and psoriasis

Yangke Cai et al. Ann Med. 2023.

Abstract

Background: Observational studies have suggested an association between inflammatory bowel disease [IBD] and psoriasis. However, the detailed genetic basis, causality, and direction of this association remain unclear.

Methods: Bidirectional two-sample Mendelian Randomization [MR] analysis was conducted using summary statistics from published genome-wide association studies. Bayesian Colocalization and multivariable MR [MVMR] analyses were performed to identify candidate variants and risk genes involved in the shared genetic basis between IBD, psoriasis, and their subtypes.

Results: Genetically predicted IBD and Crohn's disease [CD] were associated with an increased risk of psoriasis, psoriasis vulgaris [PsV], and psoriatic arthritis [PsA] (IBD on psoriasis: pooled odds ratio [OR] 1.09, 95% confidence interval [CI] 1.04-1.14, p = .0001; CD on psoriasis: pooled OR 1.10, 95% CI 1.06-1.15, p < .0001) and vice versa (psoriasis on IBD: pooled OR 1.11, 95%CI 1.02-1.21), whereas CD only exhibited a unidirectional association with psoriasis. Colocalization analysis revealed eight candidate genetic variants and risk genes (including LINC00824, CDKAL1, IL10, IL23R, DNAJC27, LPP, RUNX3, and RGS14) associated with a shared genetic basis. Among these, IL23R, DNAJC27, LPP, and RGS14 were further validated by MVMR analysis.

Conclusion: Our findings indicated bidirectional causal associations between IBD and psoriasis (including PsV and PsA), which were attributed primarily to CD rather than Ulcerative colitis [UC]. Furthermore, we identified several candidate variants and risk genes involved in the shared genetic basis of IBD and psoriasis. Acquiring a better understanding of the shared genetic architecture underlying IBD and psoriasis would help improve clinical strategies.

Keywords: Bayesian colocalization; Mendelian randomization; inflammatory bowel disease; psoriasis.

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Conflict of interest statement

The authors declare that they have no competing interests.

We are currently conducting a study on bidirectional and have encountered some confusion. I want to figure out whether bidirectional MR analysis will make extra alpha errors and lead to overestimation of causal effects? In other words, do reverse causal effects affect the estimation of forward causal effects. If so, can we use a Bonferonni-corrected threshold to mitigate this effect. I have tried my best to searched in recently published articles about bidirectional MR analysis. However, there are no relevant descriptions about the disadvantages of bidirectional MR analysis. We would be grateful if you provide some professional insights.

I sincerely value and appreciate your contributions to the development of the MR field and look forward to your reply!

Best regards,

Siyuan Xie & Delong Chen

Figures

Figure 1.
Figure 1.
Schematic overview of the study design. Step-1. Bidirectional MR study between IBD and psoriasis: The independent SNPs associated with IBD or psoriasis as genetic instrumental variables were obtained from the GWAS summary statistics for IBD from the IBD Genetic Consortium (Liu et al.) and EBI database (de Lange et al.) and psoriasis from the FinnGen and UK Biobank databases. MR analyses were performed per outcome database and subsequently analyzed. Step-2. We extracted the genomic regions extending to 200 KB of lead SNPs for COLOC analysis as a training cohort, extracted the genomic regions within a 1MB window of the genes located in the COLOC analysis as the testing cohort, and identified seven potential risk genes shared in IBD and psoriasis. In the last step, we applied univariable and multivariable MR on respective trait pairs combining genetic variants from eQTLGen and GWAS summary statistics to detect direct causal effects between IBD and psoriasis after correcting for the effects of risk genes.
Figure 2.
Figure 2.
Causal estimates for effect of IBD and subentities on psoriasis, psoriasis vulgaris and Psoriatic arthritis. Causal estimates for the effect of inflammatory bowel disease (IBD) and its subtypes, Crohn’s disease (CD) and ulcerative colitis (UC), on psoriasis (PsO), psoriasis vulgaris (PsV), and psoriatic arthritis (PsA). Estimated ORs represent the effect of per log-OR increase in IBD, CD, and UC on PsO, PsV, and PsA, obtained from an inverse-variance weighted analysis and combined over Finngen and UKB databases using meta-analyses.
Figure 3.
Figure 3.
Causal estimates for effect of psoriasis, psoriasis vulgaris and Psoriatic arthritis on IBD and its subentities. Causal estimates for the effects of psoriasis (PsO), psoriasis vulgaris (PsV), and psoriatic arthritis (PsA) on inflammatory bowel disease (IBD) and its subtypes, Crohn’s disease (CD), and ulcerative colitis (UC). Estimated ORs represent the effect of per log-OR increase in PsO, PsV, and PsA on IBD, CD, and UC, obtained from an inverse-variance weighted analysis and combined over IBDGC and EBI databases using meta-analyses.
Figure 4.
Figure 4.
Colocalization of genetic IBD and psoriasis, psoriasis vulgaris and psoriatic arthritis in genomic regions extending to 200 KB of lead SNPs. (A): rs13153019 (IBD-PsO) (B): rs11209013 (IBD-PsO), (C): rs56116661 (IBD-PsO), (D): rs11209013 (IBD-PsV) and (E): rs56116661 (IBD-PsV). For each illustration, each dot represented a genetic variant with the candidate causal variant, shown as a purple diamond. The color of other variants indicated their linkage disequilibrium (r2). The left panel showed − log10 p values for SNP associations with IBD from EBI database on the x-axes, and − log10 p values for associations with psoriasis from Finngen database on the y-axes. The right panel illustrated genomic positions based on GRCh37 on the x-axes and − log10 p values of IBD GWAS (upper panel) and − log10 p values of psoriasis (below panel) on the y-axes.
Figure 5.
Figure 5.
Colocalization of genetic crohn’s disease and psoriasis, psoriasis vulgaris and psoriatic arthritis in genomic regions extending to 200 KB of lead SNPs. (A): rs56116661 (CD-PsO) (B): rs4343432 (CD-PsV) and (C): rs4343432 (CD-PsA). For each illustration, each dot represented a genetic variant with the candidate causal variant, shown as a purple diamond. The color of other variants indicated their linkage disequilibrium (r2). The left panel showed − log10 p values for SNP associations with CD from EBI database on the x-axes, and − log10 p values for associations with psoriasis from Finngen database on the y-axes. The right panel illustrated genomic positions based on GRCh37 on the x-axes and − log10 p values of CD GWAS (upper panel) and − log10 p values of psoriasis (below panel) on the y-axes.
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Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81773065, No. 82073160);