Genetic analysis of selection bias in a natural experiment: investigating in utero famine effects on elevated body mass index in the Dutch hunger winter families study

Natural-experiment designs that compare survivors of in utero famine exposure to unaffected controls suggest that in utero undernutrition predisposes to development of obesity. However, birth rates drop dramatically during famines. Selection bias could arise if factors that contribute to obesity also protect fertility and/or fetal survival under famine conditions. We investigated this hypothesis using genetic analysis of a famine-exposed birth cohort. We genotyped participants in the Dutch Hunger Winter Families Study (DHWFS, n = 950; 45% male), of whom 51% were exposed to the 1944-1945 Dutch Famine during gestation, and 49% were their unexposed same-sex siblings or "time controls"born before or after the famine in the same hospitals. We computed body mass index (BMI) polygenic indices (PGIs) in DHWFS participants and compared BMI PGIs between famine-exposed and control groups. Participants with higher polygenic risk had higher BMIs (Pearson r = 0.42, P <. 001). However, differences between BMI PGIs of famine-exposed participants and controls were small and not statistically different from 0 across specifications (Cohen's d = 0.10, P >. 092). Our findings did not indicate selection bias, supporting the validity of the natural-experiment design within DHWFS. In summary, our study outlines a novel approach to explore the presence of selection bias in famine and other natural experiment studies.