一项全基因组跨性状分析，确定东亚人群中 Hunner 型间质性膀胱炎与自身免疫性疾病之间的共同遗传基础和因果关系。

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.

作者信息

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

机构信息

Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, Sichuan, China.

Pelvic Floor Diseases Center, West China Tianfu Hospital, Sichuan University, Chengdu, Sichuan, China.

出版信息

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

DOI:10.3389/fimmu.2024.1417899

PMID:39620209

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11604611/

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=1.09, P=1.00×10) and RA (OR=1.47, P<1.00×10) on HIC and a negative causal effect of UC on HIC (OR=0.89, P< 1.00×10). Furthermore, we unveiled a robust positive causal effect of HIC on T1D(OR=1.05, P=1.77×10). 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.

摘要

目的

流行病学研究已证明 Hunner 间质性膀胱炎（HIC）与自身免疫性疾病（ADs）之间存在临床联系，提示它们合并存在可能有共同的遗传基础。我们旨在研究 HIC 与 ADs 之间共同的遗传结构和因果关系。

方法

我们对约 170000 名东亚血统个体进行了全基因组跨性状研究，以探究 HIC 与 ADs 之间的共同结构。采用双向孟德尔随机化（MR）来评估潜在的因果关系，并进行全基因组关联研究的多性状分析（MTAG）以识别它们相关的多效性位点。精细定位分析缩小了候选基因易感位点范围，并进行共定位分析以识别特定位点的共享变异。最后，利用全转录组关联（TWAS）和功能分析来探索潜在的共享基因 - 组织关联。

结果

通过双向 MR 分析，我们观察到自身免疫性肝炎（AIH）（OR = 1.09，P = 1.00×10）和类风湿关节炎（RA）（OR = 1.47，P < 1.00×10）对 HIC 有正向因果效应，而溃疡性结肠炎（UC）对 HIC 有负向因果效应（OR = 0.89，P < 1.00×10）。此外，我们还揭示了 HIC 对 1 型糖尿病（T1D）有显著的正向因果效应（OR = 1.05，P = 1.77×10）。跨性状荟萃分析共鉴定出 64 个与 HIC 和 ADs 相关的独立单核苷酸多态性（SNPs）。功能分析表明，所鉴定的变异调节了自身免疫系统主要组织中的基因表达。