An Atlas of Modifiers of Age at Onset in Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is a fatal neurodegenerative disorder lacking effective treatment. The relationship between modifiable factors and age at onset (AAO) in HD remains controversial and causally unconfirmed. Identifying causal modifiers of AAO is crucial for delaying onset and disease prevention. METHOD: This study conducted the first comprehensive Mendelian randomization (MR) analysis of AAO causal determinants in HD. We reviewed previous observational and MR studies and identified 36 potential modifiers, of which 26 with available genetic instrument were analyzed. Summary statistics for residual AAO were obtained from the largest GWAS by the GeM-HD Consortium. The inverse-variance weighted method served as the primary analysis, with multiple sensitivity tests for robustness. Multivariable MR evaluated independent effects of exposures. RESULTS: Univariable MR identified 14 modifiers causally associated with AAO. Six previously reported factors were replicated, including telomere length, leisure screen time, coffee consumption and metabolism, smoking behaviors, diastolic blood pressure, and target effect of calcium channel blockers (CCBs). Eight novel modifiers were discovered, including education, economic status, adiposity distribution, appendicular lean mass, overall effects of CCBs, triglycerides, and target effect of lipid-lowering drugs and overall effects of statins. Multivariable MR confirmed eight independent factors: education, leisure screen time, coffee consumption, smoking behaviors, visceral adiposity, overall effects of CCBs, triglycerides, and overall effects of statin use. All associations were consistent across sensitivity analyses. CONCLUSIONS: These findings provide the most comprehensive causal landscape of AAO modifiers in HD to date, highlighting modifiable biological and lifestyle factors that may underpin future preventive or therapeutic interventions.