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

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:

• Mendelian randomization
• inflammatory bowel disease
• psoriasis
• Bayesian colocalization

Acknowledgements

We wish to acknowledge the participants and investigators of the IBDGC, EBI, FinnGen, and UK Biobank studies.

Authors contributions

YJ, MJS, and CJT designed the study and reviewed the relevant literature. CYK and CDL performed data analyses and wrote the manuscript for this study. XSY, JX, and WDH contributed to the writing of the original draft. BWW contributed to literature review. All authors have read and approved the final manuscript for submission.

Consent form

The authors confirm that the work has not been published before nor elsewhere.

Disclosure 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

Additional information

Funding

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