Common maternal and fetal genetic variants show expected polygenic effects on risk of small- or large-for-gestational-age (SGA or LGA), except in the smallest 3% of babies

Babies born clinically Small- or Large-for-Gestational-Age (SGA or LGA; sex- and gestational age-adjusted birth weight (BW) 90(th) percentile, respectively), are at higher risks of complications. SGA and LGA include babies who have experienced environment-related growth-restriction or overgrowth, respectively, and babies who are heritably small or large. However, the relative proportions within each group are unclear. We assessed the extent to which common genetic variants underlying variation in birth weight influence the probability of being SGA or LGA. We calculated independent fetal and maternal genetic scores (GS) for BW in 11,951 babies and 5,182 mothers. These scores capture the direct fetal and indirect maternal (via intrauterine environment) genetic contributions to BW, respectively. We also calculated maternal fasting glucose (FG) and systolic blood pressure (SBP) GS. We tested associations between each GS and probability of SGA or LGA. For the BW GS, we used simulations to assess evidence of deviation from an expected polygenic model. Higher BW GS were strongly associated with lower odds of SGA and higher odds of LGA (ORfetal = 0.75 (0.71,0.80) and 1.32 (1.26,1.39); ORmaternal = 0.81 (0.75,0.88) and 1.17 (1.09,1.25), respectively per 1 decile higher GS). We found evidence that the smallest 3% of babies had a higher BW GS, on average, than expected from their observed birth weight (assuming an additive polygenic model: P-fetal = 0.014, P-maternal = 0.062). Higher maternal SBP GS was associated with higher odds of SGA P = 0.005. We conclude that common genetic variants contribute to risk of SGA and LGA, but that additional factors become more important for risk of SGA in the smallest 3% of babies. Author summary Babies in the lowest or highest 10% of the population distribution of birth weight (BW) for a given gestational age are referred to as Small- or Large-for-Gestational-Age (SGA or LGA) respectively. These babies have higher risks of complications compared with babies with BW closer to the average. SGA and LGA babies may have experienced growth restriction or overgrowth, respectively, but may alternatively just be at the tail ends of the normal growth distribution. The relative proportions of normal vs. sub-optimal growth within these groups is unclear. To examine the role of common genetic variation in SGA and LGA, we tested their associations with a fetal genetic score (GS) for BW in 11,951 European-ancestry individuals. We also tested associations with maternal GS (5,182 mothers) for offspring BW, fasting glucose and systolic blood pressure, each of which influences fetal growth via the in utero environment. We found fetal and maternal GS were associated with SGA and LGA, supporting strong maternal and fetal genetic contributions to birth weight in both tails of the distribution. However, within the smallest 3% of babies, the maternal and fetal GS for BW were higher than expected, suggesting factors additional to common genetic variation are more important in determining birth weight in these very small babies.