Effects of maternal and paternal smoking on offspring cardiometabolic risk factors in adulthood: a multi-method intergenerational Mendelian randomization study

Parental smoking has been linked to several adverse offspring cardiometabolic outcomes; however, evidence is conflicting regarding the causal and long-term nature of these associations. We investigated the effects of maternal and paternal smoking, capturing exposure before, during, and after pregnancy, on eleven offspring cardiometabolic risk factors related to body composition, blood pressure, glucose, and lipid levels in adulthood. We applied a multi-method intergenerational Mendelian randomization (MR) framework, combining two-sample MR (outcome GWAS n = up to 564,160) and one-sample MR using genetic risk score (GRS) analyses (n = up to 17,484 genotyped mother, father, offspring trios with offspring cardiometabolic risk factors) from the Norwegian HUNT cohort and British UK Biobank and ALSPAC cohorts. Smoking behaviour was instrumented using genome-wide significant variants for smoking initiation and heaviness from large genome-wide association studies (2019 and 2022), with additional analyses of the CHRNA5 variant rs16969968. Using the two-sample MR approach, we found that an average change in adult offspring waist-hip-ratio (WHR) per one standard deviation (SD) increase in maternal cigarettes smoked per day of 0.25 SD (95% CI: 0.13, 0.38; 2019 GWAS), 0.19 SD (95% CI: 0.08, 0.31; 2022 GWAS) and 0.27 SD (95% CI: 0.07, 0.47; CHRNA5 rs16969968). We also found tentative evidence of comparable effects on offspring body mass index and C-reactive protein. One-sample MR analyses using CHRNA5 rs16969968, restricted to maternal ever-smokers, provided supporting evidence for a causal effect of maternal smoking heaviness on offspring WHR. We found little evidence that maternal smoking initiation affected WHR, and little evidence that maternal smoking heaviness affected the remaining cardiometabolic risk factors; paternal smoking showed no clear effect on any outcome. Results from sensitivity analyses were consistent with these main findings. Our finding of higher central adiposity in adult offspring of mothers with a propensity to smoke more heavily provides further incentive for prospective mothers to quit or reduce smoking heaviness before, during, and after pregnancy. Triangulating these findings using alternative methods would be valuable.