Recent advances in human genetics have revealed a number of genes influencing the susceptibility to obesity and related conditions, but it is likely that their contribution to disease is contingent on numerous environmental factors. As the obesity epidemic has occurred over a relatively short period of recent history, use of gene-by-year of birth analysis may be a useful approach for quantifying, in aggregate, the interaction between genetic susceptibility to obesity and the numerous known and unknown environmental factors that have changed during nutrition and health transitions globally during this recent increase in obesity rates. Evidence from one family-based longitudinal study set in the United States is showcased, which points to significant increases in the effect of common genetic variants on childhood and adulthood BMI over an 80 year period spanning from 1929 to the present. First, common genetic variants previously known to be associated with age at menarche through genome-wide association analysis were examined in aggregate using a genetic risk score approach. The menarche genetic risk score, composed of 42 single-nucleotide polymorphisms (SNPs) was significantly associated with peri-pubertal BMI in both boys and girls, but the magnitude of the association was strongly dependent on year of birth, with greater effect as birth year increased. Second, a similar approach was taken using instead a BMI genetic risk score composed of 32 common variants previously found to be associated with BMI. This score was strongly associated with adulthood BMI, waist circumference, and skinfold thickness, as expected, but the magnitude of the association increased with later year of birth. Such gene-environment interactions call for greater focus on the mechanisms by which environmental factors impact the functional output of the human genome, including how epigenetic mechanisms may be altered during social, technological, nutritional, and ecological transitions.