Exploring the effect of maternal glycemic traits on offspring cardiometabolic risk factors in adulthood: an intergenerational Mendelian randomization study

Introduction Maternal higher circulating glucose levels in pregnancy have been proposed to influence the offspring’s cardiometabolic health in adulthood through developmental mechanisms. Previous observational studies may have been subject to confounding, including by the inheritance of maternal alleles that predispose to hyperglycemia in the offspring. Objectives We aimed to test the causal effect of maternal glycemic traits on offspring cardiometabolic risk factors in adulthood. Methods Two-sample intergenerational Mendelian randomization (MR) analyses were performed. Exposures in these MR analyses were maternal fasting glucose, type 2 diabetes, and gestational diabetes. Similar paternal exposures were used as negative controls. Single Nucleotide Polymorphism (SNP)-exposure associations were obtained from recent genome-wide association studies (GWAS) of fasting glucose (61 SNPs), type 2 diabetes (210 SNPs) and gestational diabetes (8 SNPs). SNP-outcome associations were obtained from adjusted GWAS (parental genotype adjusted for offspring genotype) of adult cardiovascular outcomes which we undertook in three European cohorts (n=up to 566,132). Outcomes in these MR analyses were offspring body mass index, waist-to-hip ratio, systolic and diastolic blood pressure, blood glucose, HbA1c, total cholesterol, low- and high-density lipoprotein cholesterol, triglycerides, and C-reactive protein, measured at 24-62 years of age. Birthweight was used as a positive control. Results The crude observed positive association between maternal glycemic traits and offspring blood glucose and HbA1c completely attenuated to the null after adjusting for the offsprinǵs genotype. We found no strong evidence that higher maternal fasting glucose, type 2 diabetes, or gestational diabetes were causal for adult offspring cardiometabolic risk factors. For example, the MR analyses suggested that 1SD greater maternal fasting glucose resulted in a 0.088 (95% CI: −0.090, 0.267; P =0.331) SD difference in mean offspring BMI. Results were similar for type 2 diabetes (−0.007 SD change in BMI per unit increase in log odds; 95% CI: - 0.043, 0.030; P =0.726) and gestational diabetes (−0.016 SD change in BMI per unit increase in log odds; 95% CI: −0.105, 0.072; P =0.716). In contrast, we found strong evidence that higher maternal (but not paternal) fasting glucose, type 2 diabetes, and gestational diabetes were causal for increased offspring birthweight. Conclusions Our data suggest that maternal glucose levels do not have a major influence on offspring cardiometabolic risk factors in adulthood.