Shared genetic architecture between early-onset osteoarthritis and multiple sclerosis: Evidence from a large-scale genome-wide cross-trait analysis and validation research techniques

Lv, Shi1; Tian, Xinggui2,3; Yang, Shangyou4; Sun, Jingyi5,*; Wei, Zhijian6,*

1Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, China

2University Center of Orthopedic, Trauma, and Plastic Surgery, University Hospital Carl Gustav Carus at TUD Dresden University of Technology, Dresden, Germany

3Center for Translational Bone, Joint, and Soft Tissue Research, University Hospital Carl Gustav Carus at TUD Dresden University of Technology, Dresden, Germany

4Department of Orthopaedic Surgery, University of Kansas School of Medicine-Wichita, Kansas, USA

5Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China

6Department of Orthopaedics, Qilu Hospital of Shandong University, The Second Hospital of Shandong University, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Shandong University, Jinan, Shandong Province, China

*Correspondence to: Jingyi Sun, MD, sunjy@sdfmu.edu.cn; Zhijian Wei, MD, weizhijian2002@126.com.

Funding:This work was supported in part by grants from the Taishan Scholar Young Expert, No. tsqnz20221168 (to ZW); Tianjin Science and Technology Project, No. 21JCYBJC00920 (to ZW), No. 23JCZXJC00030 (to ZW).

This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0.

Advanced Technology in Neuroscience 3(1):p 7-15, Jan–Mar 2026. | DOI: 10.4103/ATN.ATN-D-25-00019

Abstract

Osteoarthritis and neurodegenerative diseases are both linked to chronic inflammation and immune dysregulation, but their common genetic mechanisms are not fully understood. This study aimed to explore the genetic associations and pathological mechanisms between early-onset osteoarthritis and neurodegenerative diseases through genome-wide cross-trait analyses.Leveraging large-scale genome-wide association study (GWAS) summary statistics, we applied linkage disequilibrium score regression to quantify genetic correlations between multiphenotype osteoarthritis and neurodegenerative diseases. To identify shared-risk single-nucleotide polymorphisms, Multi-Trait GWAS Analysis and Cross-Phenotype Association were utilized. Pleiotropic analysis under composite null hypothesis and multimarker genome annotation analysis were employed to detect pleiotropic loci and genes. Functional annotation and tissue-specific expression profiling were conducted to characterize the effects of pleiotropic genes. Finally, bidirectional Mendelian randomization was used to explore causal relationships, with cross-ethnic validation performed in African-ancestry populations.In this study, the linkage disequilibrium score regression uncovered a substantial genome-wide genetic correlation (rg = 0.424, P = 0.001) between early-onset osteoarthritis and multiple sclerosis. In the major histocompatibility complex region (6p21.3), nine shared loci with genome-wide significance (P_SHeT < 5×10−8) were identified, showing marked enrichment in HLA gene families. Five shared genes were validated through multiple methods, with three (HLA-DRA, HLA-DOB, TNXB) replicated in African-ancestry populations. Spatiotemporal expression analyses revealed consistently high expression of these genes in brain regions such as the dorsomedial thalamus and striatum. Two-sample Mendelian randomization showed a negative causal relationship between early-onset osteoarthritis and multiple sclerosis. However, replication in non-European cohorts indicated the absence of major histocompatibility complex region signals, highlighting population-specific genetic architecture.Overall, early-onset osteoarthritis and multiple sclerosis share an immune-related genetic basis, with major histocompatibility complex region variants and cross-tissue immune regulation as key factors in comorbidity. These findings provide new insights into the “immuno-neuro-joint” interaction mechanism and shed light for developing cross-disease therapeutic strategies.

摘要

骨关节炎与神经退行性疾病均与慢性炎症及免疫紊乱相关，但其共同的遗传机制尚未完全阐明。此研究旨在通过全基因组跨表型分析，探索早发性骨关节炎与神经退行性疾病之间的遗传关联及病理机制。此研究利用大规模全基因组关联研究(GWAS)汇总数据，采用连锁不平衡评分回归量化多表型骨关节炎与神经退行性疾病之间的遗传相关性。为识别共享风险的单核苷酸多态性，采用了多表型GWAS分析和跨表型关联分析。通过复合零假设下的多效性分析和多标记基因组注释分析检测多效性位点和基因。通过功能注释和组织特异性表达谱分析，对多效性基因的影响进行了特征描述。最后，采用双向孟德尔随机化方法探索因果关系，并在非洲裔人群中进行了跨民族验证。结果显示，连锁不平衡评分回归揭示了早期发作性骨关节炎与多发性硬化症之间存在显著的全基因组遗传相关性(rg = 0.424，P = 0.001)。在主要组织相容性复合体区域(6p21.3)，识别出9个具有全基因组显著性(P_SHeT < 5×10⁻⁸)的共享位点，这些位点在HLA基因家族中显示出显著富集。通过多种方法验证了5个共享基因，其中3个基因(HLA-DRA、HLA-DOB、TNXB)在非洲裔人群中得到复制。时空表达分析显示，这些基因在脑区如背内侧丘脑和纹状体中持续高表达。两样本孟德尔随机化分析显示，早发性骨关节炎与多发性硬化症之间存在负相关因果关系。然而，在非欧洲人群中的验证表明组织相容性复合体区域信号缺失，强调了人群特异性遗传结构。上述结果显示，早发性骨关节炎与多发性硬化症共享免疫相关的遗传基础，组织相容性复合体区域变异和跨组织免疫调节是共病的关键因素。这些发现为“免疫-神经-关节”相互作用机制提供了新见解，并为开发跨疾病治疗策略提供了启示。