A genome-wide cross-trait analysis identifying shared genetic basis and causal relationships between Hunner-type interstitial cystitis and autoimmune diseases in East Asian populations

Xinyi Lyu; Liao Peng; Xueyuan Xu; Yang Fan; Yong Yang; Jiawei Chen; Mengzhu Liu; Yuanzhuo Chen; Chi Zhang; Shiqin Yang; Sihong Shen; Jie Zhang; Xiao Zeng; Hong Shen; Deyi Luo; Yifei Lin

doi:10.3389/fimmu.2024.1417899

A genome-wide cross-trait analysis identifying shared genetic basis and causal relationships between Hunner-type interstitial cystitis and autoimmune diseases in East Asian populations

Front Immunol. 2024 Nov 15:15:1417899. doi: 10.3389/fimmu.2024.1417899. eCollection 2024.

Authors

Xinyi Lyu^#^{1

2}, Liao Peng^#^{1

2}, Xueyuan Xu^{1

2}, Yang Fan^{1

2}, Yong Yang^{3

4

5}, Jiawei Chen^{1

2}, Mengzhu Liu^{6

7}, Yuanzhuo Chen^{1

2}, Chi Zhang^{1

2}, Shiqin Yang^{1

2}, Sihong Shen^{1

2}, Jie Zhang^{1

2}, Xiao Zeng^{1

2}, Hong Shen^{1

2}, Deyi Luo^{1

2}, Yifei Lin^{8

9}

Affiliations

¹ Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, Sichuan, China.
² Pelvic Floor Diseases Center, West China Tianfu Hospital, Sichuan University, Chengdu, Sichuan, China.
³ Health Management Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
⁴ General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
⁵ Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
⁶ Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
⁷ Institute of Urology, Beijing Municipal Health Commission, Beijing, China.
⁸ Department of Urology, Lab of Health Data Science, Innovation Institute for Integration of Medicine and Engineering, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
⁹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States.

^# Contributed equally.

Abstract

Purpose: Epidemiological studies have demonstrated the clinical link between Hunner interstitial cystitis (HIC) and autoimmune diseases (ADs), suggesting potential shared genetic bases for their comorbidity. We aimed to investigate the shared genetic architecture and causal relationships between HIC and ADs.

Methods: We conducted a genome-wide cross-trait study with ~170000 individuals of East Asian ancestry to investigate the shared architecture between HIC and ADs. Bidirectional Mendelian randomization (MR) was used to assess potential causal relationships and a multi-trait analysis of GWAS (MTAG) was conducted to identify their associated pleiotropic loci. Fine-mapping analysis narrowed candidate gene susceptibility loci and colocalization analysis was performed to identify shared variants at specific locus. Lastly, transcriptome-wide association (TWAS) and functional analysis were utilized to explore potential shared gene-tissue associations.

Results: Through bidirectional MR analysis, we observed a positive causal effect of AIH(OR_IVW=1.09, P_IVW=1.00×10^-3) and RA (OR_IVW=1.47, P_IVW<1.00×10^-4) on HIC and a negative causal effect of UC on HIC (OR_IVW=0.89, P_IVW< 1.00×10^-4). Furthermore, we unveiled a robust positive causal effect of HIC on T1D(OR_ConMix=1.05, P_ConMix=1.77×10^-3). Cross-trait meta-analysis identified a total of 64 independent SNPs associated with HIC and ADs. Functional analysis revealed that the identified variants regulated gene expression in major tissues belonging to the autoimmune system.

Conclusions: Our findings might offer insights into the shared underlying etiology of HIC and ADs.

Keywords: Hunner-type interstitial cystitis; Mendelian randomization; autoimmune disorder; cross-trait analysis; genetic epidemiology.

MeSH terms

Autoimmune Diseases* / genetics
Cystitis, Interstitial* / genetics
East Asian People / genetics
Genetic Predisposition to Disease*
Genome-Wide Association Study
Humans
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide
Quantitative Trait Loci

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was funded by the National Natural Science Foundation of China (Grant No. 82270720, 32171301 and 32101206), the National Key Research and Development Program of China (Grant No. 2021YFC2009100 and 2021YFC2009102), the Natural Science Foundation of Sichuan Province (Grant No. 2022NSFSC1308), and Key Program of Science and Technology Department of Sichuan Province (Grant No. 2023YFS0102 and 2023YFS0025), and 1.3.5 project for disciplines of excellence-Clinical Research Fund, West China Hospital, Sichuan University (2023HXFH044).