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.

The authors have declared no competing interest.

This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant Numbers JP20H05696), Japan Agency for Medical Research and Development (AMED) (Grant Numbers JP22gm0010009, JP24jf0126010, JP24gm2010002), and National Institutes of Health (NIH) (Grant Number R01AR080127) to H.A., and R01AG049617 and UC2 AR082186 to ML.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Human tissue collection was approved by the Scripps Human Subjects Committee (20-7636).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The raw sequencing data generated in this study have been deposited in the dbGAP database and will be made publicly available upon acceptance of the manuscript. Publicly available datasets analyzed in this study are available from their respective repositories: single-cell RNA-seq data from Swahn et al. (2022) and OA GWAS summary statistics from Hatzikotoulas et al. (2025).