Insomnia Increases Susceptibility to Sciatica: Evidence from Mendelian Randomization and Integrative Genetic Analyses

Neuropathic pain (NP) frequently co-occurs with sleep disorders, yet the causal relationship between the two remain unclear, necessitating further investigation to elucidate their intrinsic connection.

We conducted linkage disequilibrium score regression (LDSC), Mendelian randomization (MR), multivariable mendelian randomization (MVMR) and causal analysis using summary effect estimates (CAUSE) analyses based on genome-wide association study summary statistics of six NP subtypes (FinnGen R12) and six sleep traits (UK Biobank) to verify causal associations. Multi-method combined gene prioritization screening genes, with comprehensive sensitivity analyses and bias correction performed.

Our analyses revealed that among all NP subtypes, only insomnia exerted a stable potential causal effect on sciatica. LDSC analysis revealed a significant positive genetic correlation between insomnia and sciatica (rg = 0.395, P < 0.0017). MR analyses demonstrated that insomnia significantly increased the risk of sciatica (OR = 3.15, 95% CI: 2.20-4.51, P _IVW = 3.48E-10), with robust results confirmed by multiple sensitivity analyses. CAUSE further validated a positive causal association between insomnia and sciatica (OR = 3.899, 95% CI: 1.823-8.339, P = 0.003). MVMR proved the causal association remained significant after adjustment for psychiatric disorders (P _IVW < 0.05). Heritability enrichment analysis indicated that the heritability of insomnia was mainly enriched in the central nervous system. And six potential pathogenic genes were screened via multiple integrated analytical methods. Among these candidates, EIF3KP1 and PPIP5K2 showed the strongest genetic evidence and were validated in the FinnGen database.

We identified a potential causal effect of insomnia on sciatica. The comorbidity of the two conditions may be regulated by genetic mechanisms associated with the central nervous system. EIF3KP1 and PPIP5K2 were prioritized as candidate genes, and further cellular and animal experiments are required to validate their potential as molecular targets for intervening in this comorbidity.