Molecular Pain · Nov 2, 2026
Telomere length as a systemic aging-related susceptibility marker for trigeminal neuralgia: Genetic evidence from mendelian randomization
By Adegbenro TM, He J, Polimanti R et al.
Objective: To evaluate whether genetically proxied leukocyte telomere length (TL), a systemic marker of biological aging and cumulative cellular stress, is associated with trigeminal neuralgia (TN) risk. Background: TN is a severe craniofacial pain disorder classically attributed to neurovascular compression and focal trigeminal root demyelination. However, comparable neurovascular anatomy does not always produce symptoms, suggesting that host-level biological vulnerability may influence susceptibility. Methods: We performed a two-sample Mendelian randomization study using genome-wide significant single nucleotide polymorphisms for leukocyte TL as genetic instruments. The outcome was FinnGen ICD-10 G50.0 trigeminal neuralgia. Primary analysis used inverse variance weighting (IVW), with MR-Egger, weighted median, weighted mode, and MR-PRESSO as complementary estimators. Sensitivity analyses included Steiger filtering, pleiotropy testing, heterogeneity testing, and leave-one-out analysis. Reverse MR, exploratory multivariable MR, and comparator analyses for atypical facial pain, migraine, and polyneuropathy were performed. Results: Longer genetically proxied TL was associated with lower TN risk using IVW MR (OR=0.732, p=0.008). Results were concordant across weighted median (OR=0.606, p=0.011), weighted mode (OR=0.577, p=0.017), and MR-PRESSO (OR=0.732, p=0.008), while MR-Egger was directionally consistent but nonsignificant (OR=0.671, p=0.055). Steiger-filtered IVW remained directionally consistent but attenuated to non-significance while Reverse MR was non-significant. The TL-TN association remained directionally consistent after exploratory multivariable MR conditioning and was not observed for comparator phenotypes. Conclusion: Longer genetically proxied leukocyte TL was associated with lower TN risk. These findings identify leukocyte telomere length as a candidate systemic aging-related susceptibility marker for trigeminal neuralgia and support further studies integrating telomere biology with neurovascular compression grading, trigeminal nerve morphometry, and clinical outcomes.