Smoking, alcohol consumption, and age at onset of Huntington's disease: a Mendelian randomization study

Background: Smoking and alcohol consumption have been associated with earlier age at onset (AAO) of Huntington's disease (HD) in observational studies. We conducted this Mendelian randomization (MR) study to evaluate whether these associations are causal. Methods: We selected genetic instruments for lifetime smoking (n = 462,690) and alcohol consumption (n = 941,280) based on two large genome-wide association studies (GWAS). The summary-level data for residual AAO of HD were derived from a GWAS meta-analysis carried out by the Genetic Modifiers of Huntington's disease Consortium (n = 9,064 HD patients). We conducted univariable and multivariable MR analyses to evaluate the independent impact of smoking and alcohol consumption on AAO of HD. Results: Genetically predicted lifetime smoking was causally related to an earlier AAO of HD in the univariable MR analyses (β = −2.16 years per standard deviation (SD) increase in lifetime smoking index, 95% confidence interval (CI) = −3.70 to −0.63, P = 0.006). This association persisted significant in the multivariable MR analyses after adjusting for alcohol consumption (β = −2.04 years per SD increase in lifetime smoking index, 95% CI = −3.85 to −0.22, P = 0.028). However, no significant association was found between alcohol consumption and AAO of HD. Conclusions: This study suggests that genetically predicted smoking is causally related to an earlier AAO of HD.