Pleiotropic gene mapping Reveals shared immune regulatory hubs across 15 autoimmune diseases

IF 2.1 4区医学 Q3 IMMUNOLOGY

Human Immunology Pub Date : 2026-02-01 Epub Date: 2025-12-16 DOI:10.1016/j.humimm.2025.111636

Yi Jin , Hui-Min Lu , Xing-Hao Yu

{"title":"Pleiotropic gene mapping Reveals shared immune regulatory hubs across 15 autoimmune diseases","authors":"Yi Jin , Hui-Min Lu , Xing-Hao Yu","doi":"10.1016/j.humimm.2025.111636","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Autoimmune diseases (AIDs) involve immune dysfunction with complex genetic underpinnings. This study examined genetic correlations and directional genetic associations across 15 AIDs to identify common immune pathways.</div></div><div><h3>Methods</h3><div>We retrieved GWAS summary statistics for 15 AIDs and analyzed genetic overlap using LDSC and Z-score correlations. Pleiotropy was assessed via MAGMA to assign SNPs to genes and PLACO for pleiotropic gene detection. Functional annotation (FUMA) and pathway enrichment (MAGMA, MSigDB) were performed. Two-sample Mendelian randomization (MR) explored causal links between diseases and immune cell traits.</div></div><div><h3>Results</h3><div>Primary Biliary Cholangitis (PBC) had the highest SNP-heritability (43.3 %), followed by Systemic Lupus Erythematosus (SLE) (32.84 %). Most disease pairs showed positive genetic correlations. We identified 76 pleiotropic genes, with HCP5, <em>NOTCH4</em>, and <em>SKIV2L</em> shared across all 15 diseases and concentrated in the extended MHC region. Enrichment analysis highlighted cytokine signaling, antigen presentation, and T-cell-mediated pathways. MR revealed directional genetic associations among rheumatoid arthritis (RA), SLE, and Systemic Sclerosis (SS), with PBC increasing SLE risk (OR = 1.253) and Inflammatory Bowel Disease (IBD) slightly protecting against Type 1 Diabetes (T1D) (OR = 0.959). Cell-type MR showed <em>SKIV2L</em> acting across multiple T-cell and myeloid subsets, whereas <em>NOTCH4</em> effects were confined to M2 macrophages, highlighting distinct MHC-region hubs with broad versus myeloid-focused impact.</div></div><div><h3>Conclusion</h3><div>These findings map shared genetic components and highlight pleiotropic genes, especially <em>SKIV2L</em>, <em>HCP5</em> and <em>NOTCH4</em>, linking extended-MHC architecture to T-cell and myeloid programs. They provide a genetic framework for prioritizing common pathways and cell types for biomarker development and targeted therapy.</div></div>","PeriodicalId":55047,"journal":{"name":"Human Immunology","volume":"87 2","pages":"Article 111636"},"PeriodicalIF":2.1000,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Human Immunology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0198885925004070","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/12/16 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"IMMUNOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Autoimmune diseases (AIDs) involve immune dysfunction with complex genetic underpinnings. This study examined genetic correlations and directional genetic associations across 15 AIDs to identify common immune pathways.

Methods

We retrieved GWAS summary statistics for 15 AIDs and analyzed genetic overlap using LDSC and Z-score correlations. Pleiotropy was assessed via MAGMA to assign SNPs to genes and PLACO for pleiotropic gene detection. Functional annotation (FUMA) and pathway enrichment (MAGMA, MSigDB) were performed. Two-sample Mendelian randomization (MR) explored causal links between diseases and immune cell traits.

Results

Primary Biliary Cholangitis (PBC) had the highest SNP-heritability (43.3 %), followed by Systemic Lupus Erythematosus (SLE) (32.84 %). Most disease pairs showed positive genetic correlations. We identified 76 pleiotropic genes, with HCP5, NOTCH4, and SKIV2L shared across all 15 diseases and concentrated in the extended MHC region. Enrichment analysis highlighted cytokine signaling, antigen presentation, and T-cell-mediated pathways. MR revealed directional genetic associations among rheumatoid arthritis (RA), SLE, and Systemic Sclerosis (SS), with PBC increasing SLE risk (OR = 1.253) and Inflammatory Bowel Disease (IBD) slightly protecting against Type 1 Diabetes (T1D) (OR = 0.959). Cell-type MR showed SKIV2L acting across multiple T-cell and myeloid subsets, whereas NOTCH4 effects were confined to M2 macrophages, highlighting distinct MHC-region hubs with broad versus myeloid-focused impact.

Conclusion

These findings map shared genetic components and highlight pleiotropic genes, especially SKIV2L, HCP5 and NOTCH4, linking extended-MHC architecture to T-cell and myeloid programs. They provide a genetic framework for prioritizing common pathways and cell types for biomarker development and targeted therapy.

查看原文本刊更多论文

多效基因定位揭示了15种自身免疫性疾病共有的免疫调节中心。

背景：自身免疫性疾病（AIDs）涉及具有复杂遗传基础的免疫功能障碍。本研究检测了15种艾滋病的遗传相关性和定向遗传关联，以确定常见的免疫途径。方法：检索15例艾滋病的GWAS汇总统计数据，利用LDSC和Z-score相关性分析遗传重叠。多效性通过MAGMA和PLACO分别进行基因snp和多效性检测。功能注释（fua）和途径富集（MAGMA, MSigDB）。双样本孟德尔随机化（MR）探索疾病和免疫细胞特征之间的因果关系。结果：原发性胆道性胆管炎（PBC） snp遗传率最高（43.3%），其次为系统性红斑狼疮（SLE）（32.84%）。大多数疾病对显示出正的遗传相关性。我们鉴定了76个多效性基因，其中HCP5、NOTCH4和SKIV2L在所有15种疾病中共享，并且集中在扩展的MHC区域。富集分析强调细胞因子信号，抗原呈递和t细胞介导的途径。MR揭示了类风湿关节炎（RA）、系统性红斑狼疮（SLE）和系统性硬化症（SS）之间的定向遗传关联，PBC增加SLE风险（OR = 1.253），炎症性肠病（IBD）对1型糖尿病（T1D）略有保护（OR = 0.959）。细胞型MR显示，SKIV2L作用于多个t细胞和髓细胞亚群，而NOTCH4作用仅限于M2巨噬细胞，突出了不同的mhc区域枢纽，具有广泛的影响，而不是髓细胞集中的影响。结论：这些发现绘制了共享的遗传成分，并突出了多效性基因，特别是SKIV2L、HCP5和NOTCH4，将扩展的mhc结构与t细胞和髓细胞程序联系起来。它们为生物标志物开发和靶向治疗的共同途径和细胞类型的优先排序提供了一个遗传框架。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Human Immunology 医学-免疫学

CiteScore

5.40

自引率

7.40%

发文量

107

审稿时长

12 days

期刊介绍： The journal''s scope includes understanding the genetic and functional mechanisms that distinguish human individuals in their immune responses to allografts, pregnancy, infections or vaccines as well as the immune responses that lead to autoimmunity, allergy or drug hypersensitivity. It also includes examining the distribution of the genes controlling these responses in populations. Research areas include: Studies of the genetics, genomics, polymorphism, evolution, and population distribution of immune-related genes Studies of the expression, structure and function of the products of immune-related genes Immunogenetics of susceptibility to infectious and autoimmune disease, and allergy The role of the immune-related genes in hematopoietic stem cell, solid organ, and vascularized composite allograft transplant Histocompatibility studies including alloantibodies, epitope definition, and T cell alloreactivity Studies of immunologic tolerance and pregnancy T cell, B cell, NK and regulatory cell functions, particularly related to subjects within the journal''s scope Pharmacogenomics and vaccine development in the context of immune-related genes Human Immunology considers immune-related genes to include those encoding classical and non-classical HLA, KIR, MIC, minor histocompatibility antigens (mHAg), immunoglobulins, TCR, BCR, proteins involved in antigen processing and presentation, complement, Fc receptors, chemokines and cytokines. Other immune-related genes may be considered. Human Immunology is also interested in bioinformatics of immune-related genes and organizational topics impacting laboratory processes, organ allocation, clinical strategies, and registries related to autoimmunity and transplantation.