A Genome-wide study on the genetic and causal effects of smoking in neurodegeneration.

Background: Smoking represents the largest preventable risk factor for human health, yet previous studies have failed to establish conclusive evidence regarding the causal relationship between smoking and neurodegenerative diseases. This study employs genetic correlation and Mendelian randomization analyses to investigate the potential association between smoking and neurodegenerative disorders.

Methods: This study analyzed summary data from genome-wide association studies (GWAS) on smoking and neurodegenerative diseases. Genetic correlations were evaluated using linkage disequilibrium score regression (LDSC), and causal relationships were assessed through multiple Mendelian randomization methods including inverse-variance weighted (IVW), MR-Egger regression, weighted median (WME), weighted mode (WM), and simple mode (SM). sensitivity analyses were performed to examine heterogeneity, horizontal pleiotropy, and conduct leave-one-out analysis.

Results: whether an individual had ever smoked regularly (SmkInit) is positively correlated with an increased risk of Alzheimer's disease (AD) (rg = 0.134, P = 2.74 × 10⁻⁸) and negatively correlated with the risk of Parkinson's disease (PD) (rg = - 0.100, P = 1.8 × 10⁻). cigarettes per day (CigDay) are associated with a higher risk of AD (rg = 0.162, P = 4.26 × 10⁻⁵). Smoking cessation (SmkCes) is linked to an elevated risk of AD (rg = 0.1466, P = 1.5 × 10⁻), whereas age of initiation of regular smoking (AgeSmk) is negatively correlated with AD risk (rg = - 0.181, P = 8.63 × 10⁻⁶) but positively correlated with PD risk (rg = 0.170, P = 2.0 × 10⁻). Results suggest that both SmkInit and CigDay significantly increase AD risk (OR = 1.030, P = 1.74 × 10⁻⁴; OR = 1.022, P = 5.04 × 10⁻⁴), while SmkCes is associated with a reduced risk of PD (OR = 0.638, P = 1.91 × 10⁻⁶) and amyotrophic lateral sclerosis (ALS) (OR = 0.830, P = 5.29 × 10⁻⁶).

Conclusion: This study identified significant genetic associations between smoking behaviors and neurodegenerative diseases. CigDay and SmkInit increased AD risk, while SmkCes was linked to reduced risks of PD and ALS.