Fetal Genotype and Maternal Glucose Have Independent and Additive Effects on Birth Weight

Abstract

Maternal glycemia is a key determinant of birth weight, but recent large-scale genome-wide association studies demonstrated an important contribution of fetal genetics. It is not known whether fetal genotype modifies the impact of maternal glycemia or whether it acts through insulin-mediated growth. We tested the effects of maternal fasting plasma glucose (FPG) and a fetal genetic score for birth weight on birth weight and fetal insulin in 2,051 European mother-child pairs from the Exeter Family Study of Childhood Health (EFSOCH) and the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. The fetal genetic score influenced birth weight independently of maternal FPG and impacted growth at all levels of maternal glycemia. For mothers with FPG in the top tertile, the frequency of large for gestational age (birth weight ≥90th centile) was 31.1% for offspring with the highest tertile genetic score and only 14.0% for those with the lowest tertile genetic score. Unlike maternal glucose, the fetal genetic score was not associated with cord insulin or C-peptide. Similar results were seen for HAPO participants of non-European ancestry (n = 2,842 pairs). This work demonstrates that for any level of maternal FPG, fetal genetics has a major impact on fetal growth and acts predominantly through independent mechanisms.

Figure 1

The effect of combined maternal FPG and fetal genetic score for birth weight tertiles on birth weight. Bar chart showing mean birth weight (g) corrected for sex and gestational age across combined maternal FPG and fetal genetic score for birth weight tertiles for 2,051 offspring of European ancestry. Mean birth weight for all offspring of European ancestry was 3,448 ± 10 g. The lowest tertiles of the fetal genetic score for birth weight are shown in yellow, the middle tertiles in blue, and the highest tertiles in red. GS, genetic score for birth weight.

Figure 2

The effect of combined maternal FPG and fetal genetic score for birth weight tertiles on LGA prevalence. Bar chart showing the prevalence of LGA (%) across combined maternal FPG and fetal genetic score for birth weight tertiles in participants of European ancestry. The lowest tertiles of the fetal genetic score for birth weight are shown in yellow, the middle tertiles in blue, and the highest tertiles in red. GS, genetic score for birth weight.

Figure 3

The associations for maternal FPG and fetal genetic score for birth weight with fetal insulin levels. A and B: Scatter plots with linear regression lines (in red) showing associations for maternal FPG (A) and fetal genetic score for birth weight (B) with cord insulin level at birth in EFSOCH (n = 546). C and D: Scatter plots with linear regression lines (in red) showing associations for maternal FPG (C) and fetal genetic score for birth weight (D) with cord C-peptide in HAPO (n = 1,350). Cord insulin levels ≤5 pmol/L are truncated at 5 pmol/L and levels ≥200 pmol/L are truncated at 200 pmol/L. Cord C-peptide levels ≥4 µg/L are truncated at 4 µg/L.