Abstract P225: Obesity Genetic Risk Alleles Do Not Substantially Contribute to the Association Between Gestational Diabetes Exposure and Childhood Adiposity

Abstract

Background: Prior work has demonstrated a strong association between gestational diabetes mellitus (GDM) exposure and childhood adiposity. However, it is unknown whether this association is attributable to specific intrauterine effects or merely to genetic transmission of risk alleles associated with obesity or other metabolic traits. We aimed to assess whether obesity and insulin resistance associated genetic risk alleles explain the association between gestational diabetes exposure and childhood adiposity. Study Population: Children aged 7 to 12 years enrolled in the Exploring Perinatal Outcomes in Children (EPOCH) Study who have genome-wide common variant genotyping (n=282), 82 of whom were exposed to GDM in utero and 200 of whom were not. Methods: Genetic risk scores (GRS) for body mass index (BMI) and insulin resistance (IR) were calculated by summing the count of 91 BMI-raising or 10 insulin resistance-raising risk alleles, respectively. Multivariable linear and logistic regression were used where appropriate to estimate associations between offspring GRS and maternal exposures (GDM and pre-pregnancy overweight/obesity [BMI >= 25]), as well as offspring GRS and childhood obesity traits (BMI and childhood waist circumference), adjusting for clinical and demographic covariates. Contribution of offspring GRS to association between maternal GDM or pre-pregnancy overweight/obesity and childhood adiposity was estimated by comparing the regression coefficient for the exposure variable in models with and without GRS. Results: The offspring BMI GRS was weakly associated with GDM (p=0.05), and more strongly associated with maternal pre-pregnancy overweight/obesity (p=0.001). Offspring BMI GRS was also strongly associated with childhood BMI (p=0.006) and waist circumference (p=0.02), whereas the insulin resistance GRS was not associated with GDM, maternal pre-pregnancy overweight/obesity, childhood BMI, or waist circumference. Offspring BMI genetic risk explained only 7.7% (95% CI -3.3, 18.8; p=0.2) and 5.8% (95% CI -3.1, 14.8; p=0.2) of the associations between GDM and childhood BMI and waist circumference, respectively. Similarly, offspring BMI genetic alleles explained only 4.8% (95% CI -5.4, 14.9; p=0.4) and 4.0% (95% CI -5.4, 13.4; p=0.4) of the associations between maternal pre-pregnancy overweight/obesity and childhood BMI and waist circumference, respectively. Conclusions: Genetic risk for obesity does not substantially explain the association between GDM exposure and childhood adiposity. The association between GDM and childhood adiposity is likely explained through alternative pathways, either through direct intrauterine effects or through shared postnatal environment.