Estimating the causal relationship between smoking and abdominal adiposity using Mendelian randomization

Smokers have on average lower body weight than non-smokers. However, observational studies suggest that, despite a lower body weight, smoking may lead to higher abdominal adiposity. At present, it remains unclear whether this represents a causal relationship, warranting a Mendelian randomization study. Thus, we assessed the causal relationship between smoking and abdominal adiposity using two-sample Mendelian randomization. We used published GWAS results for smoking initiation (n=1,232,091), lifetime smoking (n=462,690) and smoking heaviness (n=337,334) as the 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 the outcome traits. We implemented Mendelian randomization analyses using the recently developed CAUSE and LHC-MR methods that instrument smoking using full GWAS results rather than genome-wide significant loci only. Both CAUSE and LHC-MR indicated a positive causal effect of smoking initiation on WHR (0.13 [95%CI 0.10, 0.16] and 0.49 [0.41, 0.57], respectively) and on WHRadjBMI (0.07 [0.03, 0.10] and 0.31 [0.26, 0.37]). Similarly, they indicated a positive causal effect of lifetime 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]). The causal estimates for WCadjBMI and HCadjBMI suggested that the higher abdominal fat (i.e. higher WCadjBMI) came at the cost of lower gluteofemoral fat (i.e. lower HCadjBMI). There was no evidence of a causal effect of smoking heaviness on abdominal adiposity. However, we found evidence of reverse causality, where abdominal adiposity increased smoking heaviness. Our findings suggest that smoking initiation and higher lifetime smoking are causally associated with higher abdominal adiposity. Thus, public health efforts aimed at smoking prevention and cessation may also help reduce abdominal adiposity.