Variants near CCNL1/LEKR1 and in ADCY5 and fetal growth characteristics in different trimesters

Context: A recent genome-wide association study identified variants near CCNL1/LEKR1 (rs900400) and in ADCY5 (rs9883204) to be associated with birth weight. We examined the associations of these variants with fetal growth characteristics in different trimesters, with a main interest in the timing of the associations and the affected body proportions. Methods: We used data from two prospective cohort studies from fetal life onward in The Netherlands and Australia. Repeated fetal ultrasound examinations were performed to measure head circumference (HC), abdominal circumference (AC), femur length (FL), and estimated fetal weight (EFW). Analyses were based on a total group of 3909 subjects. Results: The C-allele of rs900400 was associated in second trimester with smaller fetal HC and FL, and in third trimester with smaller HC, AC, FL, and EFW. For each C-allele, the combined effect estimate for EFW in third trimester was - 18.6 g (95% confidence interval, -27.5, -9.7 g; P = 4.2 x 10^-5). The C-allele of rs9883204 was not associated with fetal growth characteristics in second trimester but was associated with restriction of all growth characteristics, except HC, in third trimesterandat birth. For each C-allele, thecombinedeffect estimatewas-16.9g(95%confidence interval, -26.8, -7.0 g; P = 8.4 x 10^-4) for EFW in third trimester. Both genetic variants were associated with lower birth and placenta weight. Conclusions: Our results suggest that a genetic variant of rs900400 leads to symmetric growth restriction from early pregnancy onward, whereas a genetic variant of rs9883204 leads to asymmetric growth restriction, characterized by a relatively larger HC, from third trimester.