Childhood Obesity Raises GDM Risk Through Adult Obesity: Evidence From Lifecourse Mendelian Randomization Study

Abstract BACKGROUND The relationship between childhood and adulthood obesity and the risk of gestational diabetes mellitus (GDM) remains unclear. To clarify the independent and joint effects of childhood and adulthood body size on GDM risk, and explore inflammation’s role. METHODS Using female-specific UK Biobank genome-wide association study data, genetic instruments for childhood/adult body size (“thinner,” “about average,” “plumper”) and C-reactive protein (CRP) were identified. GDM variants came from FinnGen. Univariable and multivariable Mendelian randomization (MR) assessed causality and mediation. RESULTS Univariable MR analyses provided strong evidence for genetically predicted effects of both childhood body size (odds ratio [OR] per category = 1.72, 95% CI: 1.42–2.09, P < 0.001) and adulthood body size (OR = 1.59, 95% CI: 1.42–1.79, P < 0.001) on GDM risk. However, in multivariable MR analysis, the effect of childhood body size was attenuated and no longer significant after adjusting for adulthood body size (OR = 1.19, 95% CI: 0.91–1.48, P = 0.221), whereas the effect of adulthood body size remained significant even after controlling for birth weight, childhood body size, and age at menarche (OR = 1.42, 95% CI: 1.15–1.68, P = 0.011). Further analysis indicated that CRP partially mediated the effect of adulthood body size on GDM risk. CONCLUSIONS Our findings suggest that childhood obesity increases the future risk of GDM primarily through its persistence into adulthood, and that inflammation, as indicated by elevated CRP levels, partially mediates the effect of adult obesity on GDM risk. These results highlight the importance of early obesity prevention and intervention, as well as inflammation control, to reduce the risk of GDM later in life.