Parental body mass index and offspring cardiovascular risk factors in adulthood: an intergenerational Mendelian randomization study

Importance Observationally, greater pre-pregnancy maternal and paternal body mass index (BMI) are associated with a poorer offspring adult cardiovascular risk factor profile, but it is unclear whether this is due to family-level confounding or causal developmental mechanisms. Objective We aimed to test the causal effect of maternal and paternal BMI on offspring cardiovascular risk factors in adulthood, accounting for the genetic correlation between parents and offspring. Design Two-sample intergenerational Mendelian randomization (MR) study. Genetic instruments for parental BMI (up to 495 SNPs) were obtained from the most recent genome wide association study (GWAS). Genetic associations were extracted from adjusted GWAS (parental genotype adjusted for offspring genotype) of adult cardiovascular outcomes, which we undertook in the Trondelag Health Study (HUNT), UK Biobank (UKB) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (n = up to 564,160). We conducted sensitivity analyses that are robust to different patterns of horizontal pleiotropy. Setting Norway (HUNT; MoBa) and UK (UKB and ALSPAC). Exposures Maternal and paternal BMI. Main outcomes Offspring BMI, waist-hip ratio (WHR), systolic (SBP) and diastolic (DBP) blood pressure, glucose, glycated haemoglobin (HbA1c), cholesterol, HDL-C, LDL-C, triglycerides, and C-reactive protein (CRP), measured at 24-62 years of age. Offspring birth weight was included as a positive control outcome for which we would expect to find a causal effect from maternal BMI. Results MR provided little evidence for a causal effect of maternal or paternal BMI on offspring outcomes. Differences (95% CI, P-value) in mean outcome standard deviation (SD) per 1 SD higher maternal BMI were -0.04 (-0.11, 0.04, P = 0.31) for BMI, 0.01 (-0.05, 0.06, P = 0.85) for SBP and 0.02 (-0.04, 0.09, P = 0.47) for glucose. Equivalent paternal results were 0.00 (-0.08, 0.09, P = 0.97) for BMI, -0.01 (-0.07, 0.06, P = 0.85) for SBP, and -0.05 (-0.13, 0.03, P = 0.24) for glucose. Results for other outcomes were similar, and sensitivity analyses were consistent. For birth weight, we found strong evidence for a causal effect of maternal BMI (0.10 [0.05, 0.14, P = 3.7x10-6]), but not paternal BMI (0.01 [-0.06, 0.07, P = 0.87]). Conclusions and relevance Our data suggest that neither maternal nor paternal BMI have a major influence on offspring adult cardiovascular risk factors.