BACKGROUND AND AIMS: Smokers tend to have a lower body weight than non-smokers, but also more abdominal fat. It remains unclear whether or not the relationship between smoking and abdominal obesity is causal. Previous Mendelian randomization (MR) studies have investigated this relationship by relying upon a single genetic variant for smoking heaviness. This approach is sensitive to pleiotropic effects and may produce imprecise causal estimates. We aimed to estimate causality between smoking and abdominal obesity using multiple genetic instruments.

DESIGN: MR study using causal analysis using summary effect estimates (CAUSE) and latent heritable confounder MR (LHC-MR) methods that instrument smoking using genome-wide data, and also two-sample MR (2SMR) methods.

SETTING: Genome-wide association studies (GWAS) summary statistics from participants of European ancestry, obtained from the GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN), Genetic Investigation of Anthropometric Traits (GIANT) Consortium and the UK Biobank.

PARTICIPANTS: We used GWAS results for smoking initiation (n = 1 232 091), life-time smoking (n = 462 690) and smoking heaviness (n = 337 334) as exposure traits, and waist-hip ratio (WHR) and waist and hip circumferences (WC and HC) (n up to 697 734), with and without adjustment for body mass index (adjBMI), as outcome traits.

MEASUREMENTS: Smoking initiation, life-time smoking, smoking heaviness, WHR, WC, HC, WHRadjBMI, WCadjBMI and HCadjBMI.

FINDINGS: Both CAUSE and LHC-MR indicated a positive causal effect of smoking initiation on WHR (0.13 [95% confidence interval (CI) = 0.10, 0.16 and 0.49 (0.41, 0.57), respectively] and WHRadjBMI (0.07 (0.03, 0.10) and 0.31 (0.26, 0.37). Similarly, they indicated a positive causal effect of life-time smoking on WHR [0.35 (0.29, 0.41) and 0.44 (0.38, 0.51)] and WHRadjBMI [0.18 (0.13, 0.24) and 0.26 (0.20, 0.31)]. In follow-up analyses, smoking particularly increased visceral fat. There was no evidence of a mediating role by cortisol or sex hormones.

CONCLUSIONS: Smoking initiation and higher life-time smoking may lead to increased abdominal fat distribution. The increase in abdominal fat due to smoking is characterized by an increase in visceral fat. Thus, efforts to prevent and cease smoking can have the added benefit of reducing abdominal fat.