Causal Relationships of Ligamentous Injuries in the Knee on Corticospinal Tract Structure: A Mendelian Randomization Analysis

Abstract

Background: The association between ligamentous knee injuries and corticospinal tract (CST) structure has attracted attention; however, any causal relationship remains uncertain. We performed Mendelian randomization (MR) analysis to identify the causal effects of ligamentous knee injuries on the CST. Hypothesis: Ligamentous knee injuries impair CST microstructure (ie, by reducing fractional anisotropy [FA] and increasing mean diffusivity [MD]). Study Design: MR analysis. Level of Evidence: Level 2. Methods: MR uses genetic variants as instrumental variables to infer causal relationships between exposures and outcomes. Summary data for ligamentous injuries in knee and CST structure were obtained from genome-wide association study datasets. Significant and independent (5 × 10−6; r2 < 0.001; 10,000 kb) single-nucleotide polymorphisms were extracted for MR analysis. Three methods for MR analysis were used (hypothesis-driven 1-tailed inverse variance weighted, MR-Egger, and weighted median), and sensitivity analyses were conducted to test reliability and stability. Results: Results from 3 MR methods consistently demonstrated that ligamentous knee injuries increased MD of the right CST (β, 0.063; 90% CI, 0.003-0.123; P = 0.04), and weak statistical significance suggested increased MD of the left CST (β, 0.060; 90% CI, -0.002 to -0.121; P = 0.05). However, no significant causal relationships were observed in CST FA, and no significant pleiotropy or heterogeneity was observed. Sensitivity analysis utilizing 2-tailed tests had no significant associations between ligamentous knee injuries and changes in CST structure. Conclusion: There is statistically weak genetic evidence that corticospinal pathway abnormalities may evolve after ligamentous knee injuries, which manifests as abnormally organized neurites. Clinical Relevance: Ligamentous knee injuries require attention not only to damage to the structure of the knee joint itself but also to the process of maladaptive neuroplasticity that leads to structural and functional changes of the CST; novel interventions that target the corticospinal pathway may provide subsequent treatment of ligamentous knee injuries.