Abstract
BACKGROUND: Previous studies have shown that brain volume is negatively associated with cigarette smoking, but there is an ongoing debate about 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 directionality: Bradford Hill's criteria, which are commonly used to understand a causal relationship in epidemiological studies, and mediation analysis. METHODS: In 32,094 participants of European descent from the UK Biobank dataset, we examined the relationship between a history of daily smoking and brain volumes, as well as an association of genetic risk score to ever smoking with brain volume. RESULTS: A history of daily smoking was strongly associated with decreased brain volume, and a history of heavier smoking was associated with a greater decrease in brain volume. The strongest association was between total gray matter volume and a history of daily smoking (effect size = -2964 mm(3), p = 2.04 × 10(-16)), and there was a dose-response relationship with more pack years smoked associated with a greater decrease in brain volume. A polygenic risk score for smoking initiation was strongly associated with a history of daily smoking (effect size = 0.05, p = 4.20 × 10(-84)), but only modestly associated with total gray matter volume (effect size = -424 mm(3), p = .01). Mediation analysis indicated that a history of daily smoking mediated the relationship between the smoking initiation polygenic risk score and total gray matter volume. CONCLUSIONS: A history of daily smoking is strongly associated with a decreased total brain volume.