Abstract
Fetal intrauterine growth is influenced by complex interactions between the maternal genes, environment and fetal genes. The aim of this study was to assess the effect of GWAS-identified genetic variants associated with birth weight on intrauterine fetal growth in 665 children. Fetal growth was estimated by two-dimensional ultrasound scans at 20, 25 and 32 weeks of gestation and growth trajectories were modeled using mixed linear regression. A genetic risk score (GRS) of birth weight-raising variants was associated with intrauterine growth showing an attenuating effect on the unconditional daily reduction in proportional weight gain of 8.92 × 10−6 percentage points/allele/day (p = 2.0 × 10−4), corresponding to a mean difference of 410 g at 40 weeks of gestation between a child with lowest and highest GRS. Eight variants were independently associated with intrauterine growth throughout the pregnancy, while four variants were associated with fetal growth in the periods 20–25 or 25–32 weeks of gestation, indicating that some variants may act in specific time windows during pregnancy. Four of the intrauterine growth variants were associated with type 2 diabetes, hypertension or BMI in the UK Biobank, which may provide basis for further understanding of the link between intrauterine growth and later risk of metabolic disease.
Highlights
An association between fetal growth and the occurrence of metabolic syndrome later in life was first noted by Barker et al in 19937
We evaluated the combined effect of genome-wide association study (GWAS)-identified birth weight-raising variants on intrauterine fetal growth from 20 gestational weeks to birth
We demonstrate that the birth weight-raising genetic risk score (GRS) was associated with overall intrauterine fetal growth, suggesting that the fetal genetic contribution to birth weight is mediated throughout pregnancy
Summary
An association between fetal growth and the occurrence of metabolic syndrome later in life was first noted by Barker et al in 19937. A number of genetic association studies have identified single gene variants associated with abnormal fetal growth Many of these variants are known to be associated with type 2 diabetes (T2D), maturity-onset diabetes of the young (MODY) subtypes, or rare congenital diseases leading to metabolic alterations[13,14,15,16]. Most studies have used birth weight as a surrogate of intrauterine growth and have not assessed fetal genetic effects during specific gestational growth periods. We aimed to evaluate the prenatal effect of the recently GWAS identified birth weight variants by testing the impact of variants combined in a genetic risk score (GRS) on overall fetal growth during 2nd and 3rd trimester and independently during specific. We explored if the variants associated with fetal intrauterine weight were associated with development of hypertension, T2D and BMI in adulthood using data from the UK Biobank
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