Genetic Anchoring of Stromal Cellular Programs Relevant to Ligamentum Flavum Remodeling in Lumbar Spinal Stenosis

Background/Objectives: Lumbar spinal stenosis (LSS) has a substantial inherited component, but the cellular contexts in which genetic susceptibility acts remain incompletely resolved. We integrated large-scale human genetics with a donor-resolved spinal-ligament single-cell resource and an external ligamentum flavum (LF) expression dataset to localize inherited susceptibility and prioritize regulatory candidates.

Methods

We reconstructed a nine-donor spinal-ligament single-cell resource and derived donor-aware Broad Stromal and degenerative-LSS-associated Stromal transcriptional programs. These programs were evaluated using stratified LD score regression (S-LDSC) against an LSS genome-wide association dataset of 40,303 cases and 741,468 controls, followed by gene-based association, fine-mapping, target-aware molecular colocalization, donor-robustness analyses, and external LF tissue directional sensitivity.