揭示焦虑症与自身免疫性疾病之间的遗传多效性：来自大规模全基因组跨性状分析的见解

Unveiling the genetic pleiotropy between anxiety disorders and autoimmune diseases: insights from large-scale genome-wide cross-trait analysis.

作者信息

Lin Haitao, Xiao Yao, Liu Yingqiao, Lin Xiaoyang, Liu Xiqiang

机构信息

Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

出版信息

J Affect Disord. 2025 Jul 26;391:119984. doi: 10.1016/j.jad.2025.119984.

DOI:10.1016/j.jad.2025.119984

PMID:40721144

Abstract

BACKGROUND

This study investigates the shared genetic architecture between anxiety disorders (ADs) and ten autoimmune diseases: rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), mixed connective tissue disease (MCTD), graves' disease (GD), ankylosing spondylitis (AS), Sjögren's syndrome (SS), multiple sclerosis (MS), and systemic lupus erythematosus (SLE). It aims to identify shared risk loci, key immune traits, and genetic mechanisms contributing to the pathophysiology of these conditions.

METHODS

Utilizing GWAS summary data from IEU Open GWAS and Finngen R11, we identified significant genetic correlations between ADs and autoimmune diseases. Cross-trait pleiotropy analysis identified shared loci and genes, followed by functional annotation and tissue-specific analyses. Heritability enrichment analysis highlighted critical immune cell types and tissues, while immuno-localization analysis explored disease associations.

RESULTS

34 pleiotropic loci were identified between ADs and six autoimmune diseases at genome-wide significance (P < 5 × 10), of which 4 loci (rs12624433, rs72745322, rs12967143, rs2759663) passed the causal colocalization test (PPH.4 > 0.8). Further gene-level analysis identified 83 pleiotropic genes (P < 0.05/18488 = 2.704 × 10), including PUS10, RBM4, RBM4B, and RBM5. Tissue enrichment analysis highlighted pleiotropic mechanisms in the pituitary, whole blood, and brain cerebellum. Immuno-localization analysis suggested that CD14- CD16+ monocytes play a vital role in shared genetic mechanisms between ADs and CD.

CONCLUSIONS

Our study uncovers positive genetic correlations between ADs and six autoimmune diseases-RA, CD, UC, PsO, MCTD, and SS, uncovering pleiotropic loci and genes associated with inflammation, adaptive immunity, and the PID CD40 pathway, with CD14- CD16+ monocytes potentially serving a key role in shared genetic mechanisms between ADs and CD.

摘要

背景

本研究调查了焦虑症（ADs）与十种自身免疫性疾病之间的共同遗传结构，这十种自身免疫性疾病包括：类风湿性关节炎（RA）、克罗恩病（CD）、溃疡性结肠炎（UC）、银屑病（PsO）、混合性结缔组织病（MCTD）、格雷夫斯病（GD）、强直性脊柱炎（AS）、干燥综合征（SS）、多发性硬化症（MS）和系统性红斑狼疮（SLE）。其目的是确定共同的风险位点、关键免疫特征以及导致这些疾病病理生理过程的遗传机制。

方法

利用来自IEU Open GWAS和芬兰基因库R11的全基因组关联研究（GWAS）汇总数据，我们确定了ADs与自身免疫性疾病之间的显著遗传相关性。跨性状多效性分析确定了共同的位点和基因，随后进行功能注释和组织特异性分析。遗传力富集分析突出了关键的免疫细胞类型和组织，而免疫定位分析则探索了疾病关联。

结果

在全基因组显著性水平（P < 5×10）下，在ADs与六种自身免疫性疾病之间鉴定出34个多效性位点，其中4个位点（rs12624433、rs72745322、rs12967143、rs2759663）通过了因果共定位检验（PPH.4 > 0.8）。进一步的基因水平分析确定了83个多效性基因（P < 0.05/18488 = 2.704×10），包括PUS10、RBM4、RBM4B和RBM5。组织富集分析突出了垂体、全血和小脑的多效性机制。免疫定位分析表明，CD14 - CD16 + 单核细胞在ADs与CD的共同遗传机制中起重要作用。