Telomere length as a systemic aging-related susceptibility marker for trigeminal neuralgia: Genetic evidence from mendelian randomization
Temitope M. Adegbenro, Jun He, Renato Polimanti, Raj Shrivastava, Konstantinos MargetisObjective
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.