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Preterm Birth Insights Uncovered in Gestational GWAS Meta-Analysis

NEW YORK – An international team led by investigators in Sweden and the UK has tracked down dozens of genetic variants contributing to gestational duration, including variants with maternal- or fetal-specific effects and variants falling at loci involved in preterm birth.

"The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved," co-senior and co-corresponding author Bo Jacobsson, an obstetrics and gynecology and genetics and bioinformatics researcher affiliated with the University of Gothenburg and the Norwegian Institute of Public Health, and his colleagues explained in Nature Genetics on Monday.

They noted that the new study "provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight."

With a genome-wide association study meta-analysis that included genotyping profiles and length-of-pregnancy data for nearly 195,600 mothers-to-be of European ancestry, the researchers tracked down two dozen gestational duration-related variants at 22 loci, including 16 loci not linked to gestation duration in the past. Even so, they emphasized that each associated allele appeared to have relatively modest estimated effects on the duration of pregnancy, ranging from seven hours to 27 hours apiece.

The team also performed expression quantitative loci- and tissue-specific expression-informed analyses aimed at prioritizing genes at the gestational duration-linked loci, then searched for genetic loci contributing to preterm or post-term birth using a GWAS meta-analysis that involved 18,797 early deliveries occurring earlier than 37 weeks of gestation, more than 260,200 unaffected controls delivering at 39 to 42 weeks of gestation, and 15,972 late deliveries exceeding 42 weeks of gestation.

There, the investigators identified a single locus associated with delivery post-term and half a dozen loci linked to preterm delivery, including genetic loci that overlapped between preterm birth and gestational duration more broadly.

"The present study is the largest published maternal GWAS of gestational duration and preterm delivery so far, and it is focused on women of European ancestry," Jacobsson said in an email, noting that the project has been underway for nearly 20 years and includes roughly four times more samples than a study from members of the same team going back to 2017.

From there, the investigators used phased genotyping data for 136,833 parent-child duos or trios to explore the relationships between maternal and fetal variants and their genetic effects, demonstrating that 15 of the gestation duration-associated variants most likely have maternal-specific effects.

Another seven variants appeared to have both maternal and fetal effects, the researchers reported, with five acting in the opposite direction in the fetus and mother-to-be. The remaining two variants seemed to have solely fetal effects.

The investigators also dug into the apparent antagonistic pleiotropy between maternal and fetal variants, highlighting maternal variants that stretched out the length of pregnancy but tamped down fetal variants that promoted increases in an infant's weight at birth.

Together, the findings "provide evidence of large genetic similarities between gestational duration and preterm delivery and further our understanding of the complex relationship between gestational duration and birth weight," the authors reported. "Particularly, we show that the maternal effects on birth weight are largely driven by gestational duration and that the maternal and fetal genomes have antagonistic pleiotropic effects on gestational duration and birth weight."