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ImportanceSmoking is associated with atherosclerotic cardiovascular disease, but the relative contribution to each subtype (coronary artery disease [CAD], peripheral artery disease [PAD], and large-artery stroke) remains less well understood. ObjectiveTo determine the effect of smoking on risk of coronary artery disease, peripheral artery disease, and large-artery stroke. DesignMendelian randomization study using summary statistics from genome-wide associations of smoking (up to 462,690 individuals), coronary artery disease (up to 60,801 cases, 123,504 controls), peripheral artery disease (up to 24,009 cases, 150,983 controls), and large-artery stroke (up to 4,373 cases, 406,111 controls) SettingPopulation-based study of primarily European-ancestry individuals ParticipantsParticipants in genome-wide association studies of smoking, coronary artery disease, peripheral artery disease, and stroke. ExposuresGenetic liability to smoking defined by lifetime smoking index: an integrated measure of smoking status, age at initiation, age at cessation, number of cigarettes smoked per day, and declining effect of smoking on health outcomes). Main Outcome MeasureRisk of coronary artery disease, peripheral artery disease, and large-artery stroke. ResultsGenetic liability to smoking was associated with increased risk of PAD (OR 2.13; 95% CI 1.78-2.56; P = 3.6 x 10-16), CAD (OR 1.48; 95% CI 1.25-1.75; P = 4.4 x 10-6), and stroke (OR 1.4; 95% CI 1.02-1.92; P = 0.036). Risk of PAD in smokers was greater than risk of large-artery stroke (pdifference = 0.025) or CAD (pdifference = 0.0041). The effect of smoking on ASCVD remained independent from the effects of smoking on traditional cardiovascular risk factors. Conclusions and RelevanceGenetic liability to smoking is a strong, causal risk factor for CAD, PAD, and stroke, although the effect of smoking is strongest for PAD. The effect of smoking is independent of traditional cardiovascular risk factors.

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