Investigating causal relationship between smoking behavior and global brain volume

Abstract Background Previous studies have shown that brain volume is negatively associated with cigarette smoking, but there is an ongoing debate whether smoking causes lowered brain volume or a lower brain volume is a risk factor for smoking. We address this debate through multiple methods that evaluate causality: Bradford Hill’s Criteria to understand a causal relationship in epidemiological studies, mediation analysis, and Mendelian Randomization. Methods In 28,404 participants of European descent from the UK Biobank dataset, we examined relationships between a history of daily smoking and brain imaging phenotypes as well as associations of genetic predisposition to smoking initiation with brain volume. Results A history of daily smoking is strongly associated with decreased brain volume, and a history of heavier smoking is associated with a greater decrease in brain volume. The strongest association was between total grey matter volume and a history of daily smoking (p-value = 8.28 × 10 −33 ), and there was a dose response relationship with more pack years smoked associated with a greater decrease in brain volume. A polygenic risk score (PRS) for smoking initiation was strongly associated with a history of daily smoking (p-value = 4.09 ×10 −72 ), yet only modestly associated with total grey matter volume (p-value = 0.02). Mediation analysis indicated that a history of daily smoking is a mediator between smoking initiation PRS and total grey matter volume. Mendelian Randomization showed a causal effect of daily smoking on total grey matter volume (p-value = 0.022). Conclusions These converging findings strongly support the hypothesis that smoking causes decreased brain volume.