Phenome-Wide Investigation of the Causal Associations Between Pre-Pregnancy Obesity Traits and Gestational Diabetes: A Two-Sample Mendelian Randomization Analyses

Pre-pregnancy obesity was associated with gestational diabetes in observational studies, but whether this relationship is causal remains to be determined. To evaluate whether pre-pregnancy obesity traits causally affect gestational diabetes risk, a two-sample Mendelian randomization (MR) analysis was performed utilizing summary-level statistics from published genome-wide association studies (GWAS). Obesity-related traits included body mass index (BMI), overweight, obesity, obesity class 1, obesity class 2, obesity class 3, childhood obesity, waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), percent liver fat, visceral adipose tissue volume, abdominal subcutaneous adipose tissue volume. Effect estimates were evaluated using the inverse-variance weighting method. Weighted median, MR-Egger, simple mode, and weighted mode were performed as sensitivity analyses. Genetically predicted pre-pregnancy BMI [odds ratio (OR) = 1.68; 95% confidence interval (CI): 1.45-1.95; P = 9.13 x 10-12], overweight (OR = 1.49; 95% CI: 1.21-1.85; P = 2.06 x 10-4), obesity (OR = 1.25; 95% CI: 1.18-1.33; P = 8.01 x 10-13), obesity class 1 (OR = 1.31; 95% CI: 1.17-1.46; P = 1.49 x 10-6), obesity class 2 (OR = 1.26; 95% CI: 1.16-1.37; P = 5.23 x 10-8), childhood obesity (OR = 1.33; 95% CI: 1.23-1.44; P = 4.06 x 10-12), and WHR (OR = 2.35; 95% CI: 1.44-3.83; P = 5.89 x 10-4) were associated with increased risk of gestational diabetes. No significant association was observed with obesity class 3, WC, HC, percent liver fat, visceral adipose tissue volume, or abdominal subcutaneous adipose tissue volume. Similar results were observed in sensitivity analyses. Therefore, genetically predicted pre-pregnancy obesity traits may increase the risk of gestational diabetes. Weight control before pregnancy may be beneficial to prevent gestational diabetes.