Polygenic risk and causal inference of psychiatric comorbidity in inflammatory bowel disease among patients with European ancestry

Yao Li; Charles N Bernstein; Wei Xu; Pingzhao Hu

doi:10.1186/s12967-022-03242-9

Polygenic risk and causal inference of psychiatric comorbidity in inflammatory bowel disease among patients with European ancestry

J Transl Med. 2022 Jan 27;20(1):43. doi: 10.1186/s12967-022-03242-9.

Authors

Yao Li^{1

2}, Charles N Bernstein³, Wei Xu^#^{2

4}, Pingzhao Hu^#^{5

6

7}

Affiliations

¹ Department of Biochemistry and Medical Genetics, University of Manitoba, Room 308-Basic Medical Sciences Building, 745 Bannatyne Avenue, Winnipeg, MB, R3E 0J9, Canada.
² Dalla Lana School of Public Health, University of Toronto, Toronto, ON, M5T 3M7, Canada.
³ Department of Internal Medicine and The University of Manitoba IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada.
⁴ Biostatistics Department, Princess Margaret Cancer Centre, Toronto, ON, M5G 2M9, Canada.
⁵ Department of Biochemistry and Medical Genetics, University of Manitoba, Room 308-Basic Medical Sciences Building, 745 Bannatyne Avenue, Winnipeg, MB, R3E 0J9, Canada. pingzhao.hu@umanitoba.ca.
⁶ Dalla Lana School of Public Health, University of Toronto, Toronto, ON, M5T 3M7, Canada. pingzhao.hu@umanitoba.ca.
⁷ CancerCare Manitoba Research Institute, Winnipeg, MB, R3E 0V9, Canada. pingzhao.hu@umanitoba.ca.

^# Contributed equally.

Abstract

Background: Approximately 40% of persons with inflammatory bowel disease (IBD) experience psychiatric comorbidities (PC). Previous studies demonstrated the polygenetic effect on both IBD and PC. In this study, we evaluated the contribution of genetic variants to PC among the IBD population. Additionally, we evaluated whether this effect is mediated by the expression level of the RBPMS gene, which was identified in our previous studies as a potential risk factor of PC in persons with IBD.

Materials and methods: The polygenic risk score (PRS) was estimated among persons with IBD of European ancestry (n = 240) from the Manitoba IBD Cohort Study by using external genome-wide association studies (GWAS). The association and prediction performance were examined between the estimated PRS and PC status among persons with IBD. Finally, regression-based models were applied to explore whether the imputed expression level of the RBPMS gene is a mediator between estimated PRS and PC status in IBD.

Results: The estimated PRS had a significantly positive association with PC status (for the highest effect: P-value threshold = 5 × 10^-3, odds ratio = 2.0, P-value = 1.5 × 10^-5). Around 13% of the causal effect between the PRS and PC status in IBD was mediated by the expression level of the RBPMS gene. The area under the curve of the PRS-based PC prediction model is around 0.7 at the threshold of 5 × 10^-4.

Conclusion: PC status in IBD depends on genetic influences among persons with European ancestry. The PRS could potentially be applied to PC risk screening to identify persons with IBD at a high risk of PC. Around 13% of this genetic influence could be explained by the expression level of the RBPMS gene.

Keywords: European ancestry; Genome-wide association analysis; Inflammatory bowel disease; Mediation causal inference; Polygenetic risk score; Psychiatric comorbidity; Transcriptome-wide association analysis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cohort Studies
Comorbidity
Genetic Predisposition to Disease
Genome-Wide Association Study*
Humans
Inflammatory Bowel Diseases* / complications
Inflammatory Bowel Diseases* / genetics
Multifactorial Inheritance / genetics