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.

Robin N Beaumont,Mark I Mccarthy,Andrew T Hattersley,Bridget A Knight,Marjo-Riitta Järvelin,Rachel M Freathy,Sailesh Kotecha,Sylvain Sebert,Nicholas J Timpson,Andrew R Wood,Sarah J Kotecha,Liming Liang

doi:10.1371/journal.pgen.1009191

Abstract

Babies born clinically Small- or Large-for-Gestational-Age (SGA or LGA; sex- and gestational age-adjusted birth weight (BW) <10th or >90th 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: Pfetal = 0.014, Pmaternal = 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.

Highlights

Size at birth is an important factor in new-born and infant survival
To examine the role of common genetic variation in Small for Gestational Age (SGA) and LGA, we tested their associations with a fetal genetic score (GS) for birth weight (BW) in 11,951 European-ancestry individuals
We found fetal and maternal genetic scores (GS) were associated with SGA and LGA, supporting strong maternal and fetal genetic contributions to birth weight in both tails of the distribution

Summary

Introduction

Size at birth is an important factor in new-born and infant survival. Term-born babies are most frequently admitted to the neonatal unit when born at the extremes of the birth weight distribution [1]. Small for Gestational Age (SGA; defined as birth weight adjusted for sex and gestational age that is below the 10th percentile of the population or customized standard) is often used as a proxy indicator of fetal or intrauterine growth restriction (FGR or IUGR [2]). A fetus is described as growth-restricted when it has failed to reach its growth potential due to impaired placental function [3] or due to fetal or maternal reasons, and SGA fetuses are at higher risk of adverse outcomes such as stillbirth [4]. Risks of adverse outcomes are increased in preterm babies, and underlying mechanisms in preterm SGA babies are likely to be different to those born at term. SGA and FGR are often used interchangeably since fetal growth can be difficult to measure. [2,3] they are not synonymous: not all growth-restricted fetuses are small enough to be considered SGA [5], and the SGA group itself is heterogeneous with an estimated 50–70% being constitutionally small babies with normal placental function and outcomes [6], in addition to babies expected to be small due to chromosomal anomalies [7]

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Conclusion