Contribution of maternal and fetal genetics to fetal weight throughout pregnancy and at birth

  1. Frances E Cates
  2. Olivia Wootton
  3. Jasmine X Kiley
  4. Tabitha Wishlade
  5. Ulla Sovio
  6. Gordon C S Smith
  7. Jasmine A Mack
  8. D. Stephen Charnock-Jones
  9. Hilary C Martin
  10. Catherine E Aiken
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Abstract

Background

Both fetal and maternal genomes contribute to birthweight, but the timing and relative magnitude of their effects during gestation remain unclear. Polygenic risk scores (PRSs), constructed from genome-wide association studies (GWAS), capture the cumulative influence of common birthweight-associated variants to quantify genetic predisposition to fetal growth. We constructed fetal and maternal PRSs for birthweight in two UK birth cohorts, the Pregnancy Outcome Prediction Study (POPS) and Born in Bradford (BiB), to evaluate their associations with estimated fetal weight (EFW) throughout pregnancy and with birthweight at delivery. We also investigated whether PRSs could improve risk stratification of infants born below the 10th centile by distinguishing those with pathological intrauterine growth restriction (IUGR) from those who are constitutionally small-for-gestational-age (SGA).

Methods

In POPS and BiB, we used LDpred2-auto to estimate PRSs based on the largest available maternal and fetal GWAS for birthweight. We longitudinally assessed EFW associations with PRSs using linear mixed effects models in POPS and BiB. We evaluated birthweight associations with PRSs using linear models, where birthweight was adjusted for gestational age and fetal sex. We estimated R 2 and conducted variance decomposition analyses for all models. Genetically-predicted birthweights were estimated from joint models of fetal and maternal PRSs plus ten genetic principal components (PCs). BiB analyses were conducted separately for genetically-inferred European (EUR) and South Asian (SAS) ancestry.

Results

While PRS fetus was significantly associated with EFW at baseline (∼22 weeks gestation) across cohorts, PRS mother was not. Both the interaction of PRS fetus and PRS mother with gestational age (GA) were significantly associated with EFW. The effect of PRS mother on EFW increased more quickly across gestation than the effect of PRS fetus in POPS, but this finding was not replicated in BiB. Jointly, fetal and maternal polygenic risk explained 4% of variance in EFW in POPS and 1% in BiB-EUR. In POPS, fetal and maternal PRSs showed independent contributions to EFW variance of 3% and 0.5%, respectively. Joint and univariable linear models showed significant positive associations of PRS fetus and PRS mother with observed birthweight. In POPS, PRS fetus and PRS mother accounted for ∼10% and ∼4% of variance in birthweight over covariates alone, respectively, which was replicated in BiB-EUR. Maternal and fetal genetic effects jointly explained 11% of birthweight variance in POPS, similar to BiB-EUR, at 12%; however, the variance explained was reduced by half in BiB-SAS, at 6%. Among POPS babies born <10th birthweight centile, the magnitude of the difference between observed and genetically-predicted birthweight was greater in the group judged clinically to be IUGR vs. SGA (p=0.008; point estimate=0.29, 95%CI: 0.12, 0.47).

Conclusions

Maternal and fetal PRSs jointly account for ∼11-12% of birthweight variance in European ancestry groups, but much less in a South Asian cohort. In POPS, the effect of birthweight-associated SNPs on estimated fetal weight increases more rapidly across pregnancy for maternal than for fetal genetic effects. Deviation from genetically-predicted birthweight may be a useful metric to help distinguish growth-restricted from constitutionally small babies.

  • Tweetable statement: Fetal and maternal genetics both influence fetal growth across gestation. Growth-restricted babies have greater differences between their genetically-predicted and observed birthweights compared to those who are constitutionally small.

  • Short title: Fetal and maternal genetic effects on fetal growth across gestation

  • AJOG at a Glance:

  • Why was this study conducted?

    • We used a polygenic risk score (PRS) for birthweight to evaluate the effects of fetal and maternal genetics on estimated fetal weight (EFW) and birthweight across pregnancy and at birth.

    • We also assessed how the difference between genetically-predicted and observed birthweight can help distinguish between small-for-gestational-age (SGA) babies and babies who experience intrauterine growth restriction (IUGR).

  • What are the key findings?

    • Fetal PRS accounts for ∼11-12% of variance in birthweight, while maternal PRS accounts for ∼6% in two mother-child cohorts with European ancestry.

    • In a South Asian ancestry cohort, the birthweight variance explained by the joint fetal-maternal PRS was approximately halved compared to European cohorts

    • SGA babies show smaller differences between their predicted and observed birthweights compared to IUGR babies.

  • What does this study add to what is already known?

    • This study separates the fetal and maternal genetic effects on EFW across gestation, and demonstrates that maternal genetic effects on fetal growth are more impactful at later gestations

    • We demonstrate the need to include more diverse ancestry groups in large-scale genetic studies around pregnancy and birthweight to create more representative risk scores.

    • Our findings suggest the potential use of deviation from genetically-predicted birthweight as a metric to differentiate growth-restricted (IUGR) from constitutionally small (SGA) babies.

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    1. Version published to 10.64898/2026.10.04.26364695 on medRxiv