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Background <p>Emerging epidemiological evidence shows myasthenia gravis (MG) is associated with age-related biological processes, but its mechanism of causality remains unexplained. This bidirectional Mendelian randomization (MR) study aimed to clarify the causal relationships between quantifiable biomarkers of aging and MG.</p> Methods <p>We extracted genetic instrumental variables for three aging biomarkers: telomere length, epigenetic clocks, and mitochondrial DNA copy number (mtDNA-CN) and MG from the public GWAS databases. The main causal effect estimates were obtained by the inverse variance weighted method, and supplementary sensitivity analysis was used to evaluate potential heterogeneity and pleiotropy effects.</p> Results <p>Overall, genetically predicted HannumAge and mtDNA-CN were associated with MG (OR = 0.909, 95% CI 0.834–0.991, <i>P</i> = 0.030; OR = 1.592, 95% CI 1.025–2.473, <i>P</i> = 0.039), though these associations did not survive false discovery rate (FDR) correction. Subgroup analyses showed a negative causal effect of HannumAge on early-onset MG (EOMG) (OR = 0.775, 95% CI 0.667–0.901, <i>P</i> = 0.001, <i>P</i><sub><i>FDR</i></sub> =0.005), and a potential positive association of mtDNA-CN with late-onset MG (LOMG) (OR = 1.756, 95% CI 1.030–2.995, <i>P</i> = 0.039, <i>P</i><sub><i>FDR</i></sub> =0.193). Reverse MR identified that EOMG causally increased epigenetic clocks (PhenoAge: OR = 1.056, 95% CI 1.004–1.111, <i>P</i> = 0.036; GrimAge: OR = 1.098, 95% CI 1.055–1.143, <i>P</i> &lt; 0.001; HannumAge: OR = 1.100, 95% CI 1.058–1.144, <i>P</i> &lt; 0.001), with the GrimAge and HannumAge association remaining significant after FDR correction. No evidence supported causal associations of MG/LOMG with aging biomarkers.</p> Conclusion <p>Our findings demonstrate a bidirectional causality between EOMG and epigenetic aging clocks, which indicates that there is a self-reinforcing pathophysiological cycle. The epigenetic age acceleration is both a driver and a result of the progression of EOMG. The correlation between mtDNA-CN and LOMG suggests that there may be a potential compensatory adaptation mechanism to combat chronic oxidative stress in age-related autoimmunity. These results highlight the complex and subtype-dependent contributions of biological aging to the autoimmune-mediated pathology of MG, and provide key mechanistic insights into the subtype-specific aging in MG.</p>

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Genetic insights into biological aging and myasthenia gravis: a Mendelian randomization study of telomere length, epigenetic clocks, and mitochondrial DNA copy number

  • 期刊论文

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  • 发表日期：

    2026年2月14日

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  • Wei Xiang,
  • Yining Luan,
  • Kangzhi Chen,
  • Ting He,
  • Qian Zhou,
  • Huan Yang

摘要

Background

Emerging epidemiological evidence shows myasthenia gravis (MG) is associated with age-related biological processes, but its mechanism of causality remains unexplained. This bidirectional Mendelian randomization (MR) study aimed to clarify the causal relationships between quantifiable biomarkers of aging and MG.

Methods

We extracted genetic instrumental variables for three aging biomarkers: telomere length, epigenetic clocks, and mitochondrial DNA copy number (mtDNA-CN) and MG from the public GWAS databases. The main causal effect estimates were obtained by the inverse variance weighted method, and supplementary sensitivity analysis was used to evaluate potential heterogeneity and pleiotropy effects.

Results

Overall, genetically predicted HannumAge and mtDNA-CN were associated with MG (OR = 0.909, 95% CI 0.834–0.991, P = 0.030; OR = 1.592, 95% CI 1.025–2.473, P = 0.039), though these associations did not survive false discovery rate (FDR) correction. Subgroup analyses showed a negative causal effect of HannumAge on early-onset MG (EOMG) (OR = 0.775, 95% CI 0.667–0.901, P = 0.001, PFDR =0.005), and a potential positive association of mtDNA-CN with late-onset MG (LOMG) (OR = 1.756, 95% CI 1.030–2.995, P = 0.039, PFDR =0.193). Reverse MR identified that EOMG causally increased epigenetic clocks (PhenoAge: OR = 1.056, 95% CI 1.004–1.111, P = 0.036; GrimAge: OR = 1.098, 95% CI 1.055–1.143, P < 0.001; HannumAge: OR = 1.100, 95% CI 1.058–1.144, P < 0.001), with the GrimAge and HannumAge association remaining significant after FDR correction. No evidence supported causal associations of MG/LOMG with aging biomarkers.

Conclusion

Our findings demonstrate a bidirectional causality between EOMG and epigenetic aging clocks, which indicates that there is a self-reinforcing pathophysiological cycle. The epigenetic age acceleration is both a driver and a result of the progression of EOMG. The correlation between mtDNA-CN and LOMG suggests that there may be a potential compensatory adaptation mechanism to combat chronic oxidative stress in age-related autoimmunity. These results highlight the complex and subtype-dependent contributions of biological aging to the autoimmune-mediated pathology of MG, and provide key mechanistic insights into the subtype-specific aging in MG.