Investigating causality in associations between education and smoking: A two-sample Mendelian randomization study

Background: Lower educational attainment is associated with increased rates of smoking, but ascertaining causality is challenging. We used two-sample Mendelian randomization (MR) analyses of summary statistics to examine whether educational attainment is causally related to smoking. Methods and Findings: We used summary statistics from genome-wide association studies (GWAS) of educational attainment and a range of smoking phenotypes (smoking initiation, cigarettes per day, cotinine levels and smoking cessation). Of 74 single nucleotide polymorphisms (SNPs) that predict educational attainment, 57 (or their highly correlated proxies) were present in the smoking initiation, cigarettes per day and smoking cessation GWAS, and 72 in the cotinine GWAS. Various complementary MR techniques (inverse variance weighted regression, MR Egger, weighted median regression) were used to test the robustness of our results. We found broadly consistent evidence across these techniques that higher educational attainment leads to reduced likelihood of smoking initiation, reduced heaviness of smoking among smokers (as measured via self-report [e.g. inverse variance weighted beta -2.25, 95% confidence interval (CI) -3.81, -0.70, P=0.005] and cotinine levels [e.g. inverse variance weighted beta -0.34, 95% CI -0.67, -0.01, P=0.057]), and greater likelihood of smoking cessation among smokers (inverse variance weighted beta 0.65, 95% CI 0.35, 0.95, P=5.54×10^-5). Less consistent across the different techniques were associations between educational attainment and smoking initiation. Conclusions: Our findings indicate a causal association between low educational attainment and increased risk of smoking, and may explain the observational associations between educational attainment and adverse health outcomes such as risk of coronary heart disease.