Perinatal Laboratory

Perinatal Laboratory

Research group

Publications

Time-varying effects are common in genetic control of gestational duration

Published in Hum Mol Genet., 2023

Abstract Preterm birth is a major burden to neonatal health worldwide, determined in part by genetics. Recently, studies discovered several genes associated with this trait or its continuous equivalent-gestational duration. However, their effect timing, and thus clinical importance, is still unclear. Here, we use genotyping data of 31 000 births from the Norwegian Mother, Father and Child cohort (MoBa) to investigate different models of the genetic pregnancy 'clock'. We conduct genome-wide association studies using gestational duration or preterm birth, replicating known maternal associations and finding one new fetal variant. We illustrate how the interpretation of these results is complicated by the loss of power when dichotomizing. Using flexible survival models, we resolve this complexity and find that many of the known loci have time-varying effects, often stronger early in pregnancy. The overall polygenic control of birth timing appears to be shared in the term and preterm, but not very preterm, periods and exploratory results suggest involvement of the major histocompatibility complex genes in the latter. These findings show that the known gestational duration loci are clinically relevant and should help design further experimental studies.


Recommended citation:
Juodakis J, Ytterberg K, Flatley C, Sole-Navais P, Jacobsson B. (2023). "Time-varying effects are common in genetic control of gestational duration." Hum Mol Genet. 32(14). http://academicpages.github.io/files/paper3.pdf

New genetic loci associated with gestational duration…

Published in Nature genetics, 2023

Abstract A GWAS meta-analysis, combined with tracing the parental transmitted and non-transmitted alleles in parent–offspring pairs, enabled us to distinguish the effects of maternal and fetal genomes on gestational duration and their links with birth weight. The identified genes are more likely to be differentially expressed during labor and show signs of antagonistic pleiotropy with fetal genome effects on birth weight.


Recommended citation:
Pol Solé-Navais, et al. (2023). " New genetic loci associated with gestational duration show a complex link with birth weight." Nat Genet. 55(1). https://www.nature.com/articles/s41588-023-01344-8

Genetic effects on the timing of parturition and links to fetal birth weight

Published in Nature genetics, 2023

Abstract The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed seven associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal–fetal relationship between gestational duration and birth weight.


Recommended citation:
Solé-Navais, P., Flatley, C., Steinthorsdottir, V. et al. " Genetic effects on the timing of parturition and links to fetal birth weight." Nat Genet 55, 559-567 (2023). https://doi.org/10.1038/s41588-023-01343-9

Exploring the impact of parity and its interaction with history of preterm delivery on gestational duration

Published in medRxiv, 2023

Abstract Delivering preterm is the leading cause of death in neonates and children under five years of age. Both genetics and environmental factors play a role in timing of delivery, and these influences can be unique to a single pregnancy or shared across pregnancies of the same mother. The aim of this study was to understand how gestational duration is affected by parity and how parity modifies the association between history of preterm delivery and gestational duration. To investigate this, we analysed 1 118 318 spontaneous deliveries (1990 - 2012) from the Swedish Medical Birth Register, with access to pedigrees, using linear regressions and linear mixed models. We found that parity has a modest effect on the mean and a large effect on the variance of gestational duration. Interactions with a woman's clinical and family history of preterm delivery revealed both pregnancy-specific and shared factors. For instance, the effect of a previous preterm delivery on gestational duration is present across pregnancies, but the magnitude of its effect is pregnancy specific. The access to pedigrees made it possible to apply linear mixed models, thus including all woman's pregnancies in the model and accounting for unobserved mother-specific covariates. The linear mixed models highlighted a group effect bias when using linear regression to estimate the association between parity and gestational duration, likely caused by socioeconomic factors. Our study shed light on how parity affects gestational duration and modifies the effect of well-known risk factors of preterm delivery.


Recommended citation:
Ytterberg, K., Jacobsson, B., Flatley, C., Juodakis, J., Nilsson, S., Solé-Navais, P. (2023). "Exploring the impact of parity and its interaction with history of preterm delivery on gestational duration. https://www.medrxiv.org/content/10.1101/2023.02.16.23286023v1