Mendelian randomization case-control PheWAS in UK Biobank shows evidence of causality for smoking intensity in 28 distinct clinical conditions

BACKGROUND: Smoking is one of the greatest threats to public health worldwide. We integrated phenome-wide association study (PheWAS) and Mendelian randomization (MR) approaches to explore causal effects of genetically predicted smoking intensity across the human disease spectrum. METHODS: We conducted PheWAS case-control analyses in 152,483 ever smokers of White-British ancestry, aged 39–73 years. Disease diagnoses were based on hospital inpatient and mortality registrations. Smoking intensity was instrumented by four genetic variants, and disease risks estimated for one cigarette per day heavier intakes. Associations passing the FDR threshold (p<0•0025) were assessed for causality using several complementary MR approaches. FINDINGS: Genetically instrumented smoking intensity was associated with 48 conditions, with MR supporting a possible causal effect for 28 distinct outcomes. Each cigarette smoked per day elevated the odds of respiratory diseases by 5% to 33% (nine distinct diseases, including pneumonia, emphysema, obstructive chronic bronchitis, pleurisy, pulmonary collapse, respiratory failure) and the odds of circulatory disease by 5% to 23% (seven diseases, including atherosclerosis, myocardial infarction, congestive heart failure, arterial embolisms). Further effects were seen for cancer within the respiratory system and other neoplasms, renal failure, septicaemia, and retinal disorders. No associations were observed in sensitivity analyses on 185,002 never smokers. INTERPRETATION: These genetic data demonstrate the substantial adverse health impacts by smoking intensity and suggest notable increases in the risks of several diseases. Public health initiatives should highlight the damage caused by smoking intensity and the potential benefits of reducing or ideally quitting smoking.