Prenatal famine exposure restricts genetic effects on birth weight with implications for metabolic disease risk

Background: Prenatal growth is shaped by genetic and environmental influences. Prenatal exposure to famine, particularly later in gestation, stunts growth and leads to lower birth weight. Here, we evaluated the effect of prenatal famine exposure on the expression of genetic influences on birth weight and how this relationship shapes associations between the early environment and metabolic disease risk in later life. Methods: We analysed data from the Dutch Hunger Winter Families Study, including 283 individuals conceived in the months before the 1944–45 Dutch Famine and therefore exposed during mid-to-late gestation, 145 conceived during the famine and thus exposed in early gestation, and 161 unexposed controls with available obstetric records and genetic data. Genetic influences on birth weight were assessed using a polygenic index (PGI). We tested for gene-environment interactions between the birth weight PGI and the timing of famine exposure, and examined whether deviations from genetically predicted birth weight were associated with fasting glucose and waist circumference in adulthood. Results: While the birth weight PGI explains 14% of the variation in birth weight in controls (r = 0.38, p < 0.001), genetics does not have a detectable influence on birth weight in famine-exposed individuals, particularly those exposed in mid-to-late gestation (r = 0.10, p = 0.09) (p_interaction<0.001). Six decades later, being born lighter than genetically predicted is associated with increased fasting glucose levels and waist circumference in those exposed to famine in mid-to-late gestation as compared to controls (p_interaction<0.04). Conclusions: Prenatal exposure to famine during mid-to-late gestation overrides genetic influences on birth weight and modifies the relationships that are observed between birth weight and metabolic risk factors in later life.