Multi-omics Mendelian randomization prioritizes BMP6 as a candidate therapeutic target in intervertebral disc degeneration.

BACKGROUND

Intervertebral disc degeneration (IVDD) is a prevalent condition causing substantial pain, muscle weakness, and functional impairment; however, the efficacy of current treatments remains limited. Therefore, candidate therapeutic targets must urgently be prioritized to guide future mechanistic and translational research. This study aims to identify genetic factors associated with IVDD and explore the underlying mechanisms through the comprehensive integration of multi-omics data.

METHODS

We applied Mendelian randomization (MR) to prioritize candidate therapeutic genetic targets for IVDD using genome-wide summary statistics from the FinnGen consortium, with UK Biobank data serving as replication cohorts. We employed expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs) to validate therapeutic targets at the transcriptomic and proteomic levels. We also integrated sensitivity, colocalization, SMR, genetic correlation, and reverse MR analyses. We applied PheWAS and drug prediction to assess off-target effects and evaluate therapeutic potential, respectively. Finally, we explored the potential mediation effects of candidate metabolites.

RESULTS

We identified seven potential therapeutic targets significantly associated with IVDD risk across the FinnGen and UK Biobank cohorts. Bayesian colocalization analysis revealed strong evidence for shared causal variants at the DLK1 (PP.H4 = 0.94) and BMP6 (PP.H4 = 0.99) loci. The BMP6 cis-eQTL met the significance thresholds for SMR (p < 0.05) and HEIDI (p > 0.05). Protein-level MR analysis demonstrated that BMP6 significantly increased IVDD risk (OR = 1.19, 95% CI 1.09-1.30; p < 0.001), supported by a colocalization probability of 99% (PP.H4 = 0.99). Additionally, BMP6 satisfied the established validation thresholds in protein-level SMR and HEIDI analyses. Consequently, BMP6 was prioritized as a candidate therapeutic target for IVDD in subsequent analyses. Urate levels exhibited a nominal mediation signal linking BMP6 to IVDD (proportion mediated = 7.48%, p = 0.036), which remained suggestive after BH-FDR correction.

CONCLUSIONS

We prioritized BMP6 as a candidate therapeutic target for IVDD and identified circulating urate as a potential mediator based on a suggestive mediation signal. These findings offer new mechanistic insights into the potential relationship between BMP6, urate metabolism, and IVDD. This gene and its associated metabolite represent promising targets for IVDD intervention and may inform subsequent translational research and preclinical validation.