Abstract
Background:Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG.Participants and methods:A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight).Results:Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10−8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG.Conclusions:We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.
Highlights
IntroductionHigh and low levels of gestational weight gain (GWG), defined as the weight a woman gains during pregnancy before delivery of her infant,[1] are associated with a wide range of adverse outcomes for mother and child in the short term (during pregnancy and the perinatal period), and long term.[2,3,4,5,6,7,8,9] As a consequence of these associations, recommendations for healthy GWG are increasingly used in antenatal care,[1] despite a lack of evidence that any of these associations are causal, and if they are, what the mechanisms underlying them might be.[3,10] GWG is a complex phenotype that is influenced by maternal responses to pregnancy, such as gestational fat deposition and volume expansion, as well as fetal growth, placental size and amniotic fluid volume.[3,10] Each of these are likely to be influenced both by maternal and fetal genes and environmental exposures
single nucleotide polymorphism (SNP) across the genome explained broadly similar proportions of variation in late gestational weight gain (GWG) and early GWG, but with stronger contributions of maternal compared with fetal genome, with SNPs in the maternal genome explaining approximately twice the amount of variation in total GWG than the fetal genome (Table 2)
The opposite pattern was seen for birth weight, for example, SNPs across the maternal genome explained 24% (P = 1.94 × 10 − 6) of the variation in total GWG, with 12% (P = 0.008) explained by SNPs in the fetal genome, whereas the maternal genome explained 13% (P = 0.02) and fetal genome 18% (P = 1.86 × 10 − 3) of variation in birth weight (Table 2)
Summary
High and low levels of gestational weight gain (GWG), defined as the weight a woman gains during pregnancy before delivery of her infant,[1] are associated with a wide range of adverse outcomes for mother and child in the short term (during pregnancy and the perinatal period), and long term.[2,3,4,5,6,7,8,9] As a consequence of these associations, recommendations for healthy GWG are increasingly used in antenatal care,[1] despite a lack of evidence that any of these associations are causal, and if they are, what the mechanisms underlying them might be.[3,10] GWG is a complex phenotype that is influenced by maternal responses to pregnancy, such as gestational fat deposition and volume expansion, as well as fetal growth, placental size and amniotic fluid volume.[3,10] Each of these are likely to be influenced both by maternal and fetal genes and environmental exposures. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight). CONCLUSIONS: We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG
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