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Integrated mapping of human meniscus and cartilage eQTLs reveals shared and distinct osteoarthritis genetic drivers

Uchida, Y.; Fujii, Y.; Swahn, H.; Ueda, M. T.; Chiba, T.; Matsushima, T.; Naito, Y.; Nakamichi, R.; Takahashi, K.; Olmer, M.; The RE-JOIN Consortium Investigators, ; Lotz, M.; Kochi, Y.; Asahara, H.

2026-04-16 orthopedics
10.64898/2026.04.12.26350702 medRxiv
Show abstract

Osteoarthritis (OA) is a prevalent musculoskeletal disorder and a leading cause of global disability. Although meniscal damage is a major risk factor of OA pathogenesis, genetic regulatory studies have remained largely confined to articular cartilage. Here, we establish the first comprehensive expression quantitative trait locus (eQTL) map integrating whole-genome sequencing and bulk transcriptomics from human meniscus (n=112) and cartilage (n=113). Supported by single-nucleus multiomics (cartilage: 56,549 nuclei; meniscus: 34,343 nuclei), we uncovered highly tissue-specific genetic risk architectures. Colocalization with OA GWAS identified 27 meniscus-specific, 28 shared, and 20 cartilage-specific causal genes. Chromatin-informed fine-mapping and deconvolution elucidated distinct pathogenic mechanisms; notably, meniscus-specific signals converged on VEGFA via rare promoter variants and an enhancer in fibrochondrocyte progenitors, alongside a shared eQTL for CLEC18A. Exploratory analysis suggested candidate compounds to reverse pathogenic gene expression. Our findings underscore the meniscus as a distinct genetic driver, molecularly reinforcing OA as an entire joint organ failure.

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