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

JOURNAL/atin/04.03/02274269-990000000-00014/figure1/v/2025-09-25T132227Z/r/image-tiff 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.