We describe a systematic approach to derive and validate a GPS, incorporating information from 2.1 million common genetic variants, to predict polygenic susceptibility to obesity and tested the polygenic score in 306,135 participants from four cohorts. The GPS accurately predicted striking differences in weight, severe obesity, cardiometabolic disease and overall mortality in middle-aged adults, with the extreme of the GPS distribution inheriting susceptibility to obesity equivalent to rare monogenic mutations in MC4R. The score had minimal association with birthweight, but it was strongly associated with a gradient in weight that started to emerge in early childhood and even larger differences in weight and severe obesity in subsequent decades.
