Causality of genetically determined serum metabolites on lower back pain or/and sciatica: a comprehensive Mendelian randomized study.

Background: There is an urgent need to confirm biomarkers reflecting the pathogenesis and targeted drugs of lower back pain or/and sciatica in clinical practice. This study aimed to conduct a two sample bidirectional Mendelian randomization (MR) analysis to explore the causal link between 486 serum metabolites and lower back pain or/and sciatica.

Methods: All data come from two public shared databases of European ancestry and single nucleotide polymorphisms (SNPs) for lower back pain or/and sciatica acted as instrumental variables. The traditional inverse variance weighting (IVW) method, weighted-median method, MR-Egger methodand other methods were used to estimate causality. The horizontal pleiotropy, heterogeneities were also verified through the MR-Egger intercept test, Cochran's Q test, MR-PRESSO test and the leave-one-out sensitivity analysis. Reverse MR analysis was employed to evaluate the direct impact of metabolites on lower back pain or/and sciatica. Additionally, we conducted the colocalization analysis to reflect the causality deeply. Furthermore, metabolic pathway analysis was performed.

Results: 28 metabolites (18 known metabolites, 1 identified metabolites and 9 unknown metabolites) relevant to the risk of sciatica or/and lower back pain after using genetic variants as probes at P_IVW < 0.05 were identifed. Among them, 8 serum metabolites decreased risk of sciatica or/and lower back pain significantly (P < 0.05), and 14 serum metabolites increased risk of sciatica or/and lower back pain significantly (P < 0.05). No reverse causal association was found between 28 metabolites and sciatica or/and lower back pain. Colocalization analysis results showed that the associations between sciatica or/and lower back pain and the 28 identified metabolites were not due to shared causal variant sites. Moreover, pathway enrichment analysis identifed 11 signifcant metabolic pathways, which are mainly involved in the pathological mechanism of sciatica or/and lower back pain (P < 0.05). There was no horizontal pleiotropy or heterogeneity in the other analyses.

Conclusion: Our analyses provided robust evidence of causal associations between blood metabolites on sciatica or/and lower back pain. However, the underlying mechanisms remain to be further investigated.