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

Genetically predicted HannumAge was negatively associated with overall MG risk, though this association did not survive FDR correction.

• OR = 0.909, 95% CI 0.834–0.991, P = 0.030
• The association did not survive false discovery rate (FDR) correction
• Estimated using the inverse variance weighted (IVW) method as the primary causal effect estimator
• Genetic instrumental variables were extracted from public GWAS databases

Genetically predicted mitochondrial DNA copy number (mtDNA-CN) was positively associated with overall MG risk, though this association did not survive FDR correction.

• OR = 1.592, 95% CI 1.025–2.473, P = 0.039
• The association did not survive false discovery rate (FDR) correction
• Estimated using the inverse variance weighted method as the primary analysis
• Sensitivity analyses were used to evaluate potential heterogeneity and pleiotropy effects

HannumAge had a significant negative causal effect on early-onset MG (EOMG) that survived FDR correction.

• OR = 0.775, 95% CI 0.667–0.901, P = 0.001
• PFDR = 0.005, indicating the association survived false discovery rate correction
• This subgroup-specific finding was identified in subgroup analyses stratifying MG by onset age

mtDNA-CN showed a potential positive association with late-onset MG (LOMG), though this did not survive FDR correction.

• OR = 1.756, 95% CI 1.030–2.995, P = 0.039
• PFDR = 0.193, indicating the association did not survive false discovery rate correction
• Identified in subgroup analyses stratifying MG by onset age

Reverse MR analysis found that EOMG causally increased multiple epigenetic clocks, with GrimAge and HannumAge associations surviving FDR correction.

• PhenoAge: OR = 1.056, 95% CI 1.004–1.111, P = 0.036 (did not survive FDR correction)
• GrimAge: OR = 1.098, 95% CI 1.055–1.143, P < 0.001 (survived FDR correction)
• HannumAge: OR = 1.100, 95% CI 1.058–1.144, P < 0.001 (survived FDR correction)
• Reverse MR was conducted to assess whether MG subtypes causally influence aging biomarkers

No evidence supported causal associations of overall MG or LOMG with any of the biological aging biomarkers in reverse MR analyses.

• Reverse MR was performed for overall MG, EOMG, and LOMG subgroups
• Only EOMG showed significant reverse causal effects on epigenetic clocks
• LOMG did not demonstrate causal effects on telomere length, epigenetic clocks, or mtDNA-CN

The study identified a bidirectional causality between EOMG and epigenetic aging clocks, suggesting a self-reinforcing pathophysiological cycle.

• Forward MR showed HannumAge negatively predicts EOMG (OR = 0.775, PFDR = 0.005)
• Reverse MR showed EOMG increases GrimAge (OR = 1.098, P < 0.001) and HannumAge (OR = 1.100, P < 0.001) with both surviving FDR correction
• Authors interpret this as indicating 'epigenetic age acceleration is both a driver and a result of the progression of EOMG'
• The study used a Mendelian randomization design to infer causality from observational GWAS data

Three categories of biological aging biomarkers were investigated as genetic instrumental variables: telomere length, epigenetic clocks (PhenoAge, GrimAge, HannumAge), and mitochondrial DNA copy number.

• Genetic instrumental variables were extracted from public GWAS databases
• The inverse variance weighted method was used as the main causal effect estimator
• Sensitivity analyses were conducted to evaluate potential heterogeneity and pleiotropy
• Bidirectional MR design was employed to assess both forward and reverse causal directions
• Subgroup analyses were performed for early-onset MG (EOMG) and late-onset MG (LOMG)