Polygenic Prediction of Weight and Obesity Trajectories from Birth to Adulthood

Severe obesity is a rapidly growing global health threat. Although often attributed to unhealthy lifestyle choices or environmental factors, obesity is known to be heritable and highly polygenic; the majority of inherited susceptibility is related to the cumulative effect of many common DNA variants. Here we derive and validate a new polygenic predictor comprised of 2.1 million common variants to quantify this susceptibility and test this predictor in more than 300,000 individuals ranging from middle age to birth. Among middle-aged adults, we observe a 13-kg gradient in weight and a 25-fold gradient in risk of severe obesity across polygenic score deciles. In a longitudinal birth cohort, we note minimal differences in birthweight across score deciles, but a significant gradient emerged in early childhood and reached 12 kg by 18 years of age. This new approach to quantify inherited susceptibility to obesity affords new opportunities for clinical prevention and mechanistic assessment. [Display omitted] •A genome-wide polygenic score can quantify inherited susceptibility to obesity•Polygenic score effect on weight emerges early in life and increases into adulthood•Effect of polygenic score can be similar to a rare, monogenic obesity mutation•High polygenic score is a strong risk factor for severe obesity and associated diseases A genome-wide polygenic score quantifies inherited susceptibility to obesity, integrating information from 2.1 million common genetic variants to identify adults at risk of severe obesity.