Causal Effects of Plasma Metabolites on Intervertebral Disc Degeneration and Low Back Pain: A Mendelian Randomization Study

Background: Metabolic disturbances have been implicated in intervertebral disc degeneration (IVDD) and low back pain, but the contribution of circulating metabolites remains uncertain. Objectives: We examined associations of genetically proxied plasma metabolites and metabolite ratios with IVDD outcomes defined at different anatomical locations and with a related pain phenotype. Methods: Summary statistics for metabolite exposures were obtained from the Canadian Longitudinal Study on Ageing (CLSA) plasma metabolome genome-wide association study (GWAS). The outcomes were Intervertebral Disc Degeneration of Cervical Spine (IVDD_Cervical), Intervertebral Disc Degeneration of Thoracic, Thoracolumbar, and Lumbosacral Spine (IVDD_TTL), and Low Back Pain (Pain_Lowback). IVDD_Cervical and IVDD_TTL represented IVDD outcomes defined at different anatomical locations of the spine, whereas Pain_Lowback was analysed separately as an IVDD-related pain phenotype. One genome-wide significant sentinel single-nucleotide variant (SNV) was used for each exposure, and Mendelian randomization (MR) estimates were calculated with the Wald ratio. The within-outcome Bonferroni threshold was 6.25 × 10−4. Results: Eighty metabolites and metabolite ratios were evaluated. Two associations were significant, both for IVDD_TTL. Higher genetically proxied dimethylarginine (SDMA + ADMA), mapped to DDAH1, was associated with lower IVDD_TTL risk (odds ratio [OR] = 0.80; 95% confidence interval [CI]: 0.72–0.90; p = 2.5 × 10−4), whereas higher alpha-hydroxyisovalerate, mapped to LDHA, was associated with higher risk (OR = 1.08; 95% CI: 1.04–1.13; p = 4.6 × 10−4). No significant association was identified for IVDD_Cervical or Pain_Lowback; 23 associations were classified as suggestive significant. DrugBank annotation identified compounds interacting with DDAH1 and LDHA. Conclusions: The results highlight DDAH1-linked methylarginine metabolism and LDHA-linked glycolytic and lactate-related biology as candidate pathways for IVDD_TTL. Findings for IVDD_Cervical, Pain_Lowback, and cross-outcome overlap remain exploratory.