March of Dimes scientists at the Ohio Collaborative Prematurity Research Center (PRC) have joined forces with leading universities in the U.S. and Europe to harness the power of international scientific collaboration and conduct the second ever large-scale Genome-Wide Association Study (GWAS) on preterm birth and gestational duration.
The study, whose findings were published last spring in Nature Genetics, added hefty evidence to genetics playing an undeniably sizable role in preterm birth, with seven regions of the maternal genome associated with early labor. It also found 22 genomic regions to be associated with gestational duration, or the length of time a woman carries a baby before the start of labor.
These regions, or variants, in the human genome gain significance based on the alleles that reside there. An allele is a variant of the sequence of nucleotides (i.e., genetic code) at a particular location on a DNA molecule. Alleles are the deciders of DNA: they influence the outcome of countless human traits such as eye color, hair color, height, and in the case of this study, gestational duration and preterm birth.
Perhaps most fascinatingly, however, the study discovered, for the first time, that there exists a complex, sophisticated, and elegant relationship around birth timing between a woman and the fetus she is carrying.
The Ohio PRC team, along with a global collective of authors that included first and senior authors from the University of Gothenburg in Sweden, found that a mom and her in-utero baby are capable of working together to counteract the effects of the mother’s genetic variants related to birth timing to benefit the health of the pregnancy.
Specifically, they found that if a mom and baby share the same alleles at the same genetic regions—for the mom, at the regions responsible for gestational duration, and for the baby, at the regions that can influence fetal growth—the effects are balanced for an optimal outcome.
In other words, moms who have a genetic predisposition to go to 40 weeks or beyond will initiate a genetic process with her baby’s DNA to slow the baby’ growth to facilitate a healthy birth.
“This finding was simply fascinating,” said Ohio PRC investigator and senior study author Dr. Ge Zhang, who serves as a Professor in the Department of Pediatrics at the University of Cincinnati’s College of Medicine and as the leader of the Pregnancy Genomics Lab at the Division of Human Genetics at the Cincinnati Children’s Hospital. “If a fetus grows faster and the mother has a long gestational duration it will increase the burden on the mother. This co-adaptation we’ve identified could be one of the natural solutions for that problem: if the baby grows faster or slower, the mother’s genetic variants for gestational duration will shorten or lengthen duration to compensate.”
“This discovery not only shows the beauty and brilliance of the mother-baby dyad in the overall fitness of a pregnancy, but it lends additional evidence to the powerful role of genetics in the length of gestation and preterm birth.”
Dr. Zhang and fellow senior study author Dr. Bo Jacobsson from Sweden’s University of Gothenburg found that of the 22 genomic loci, or regions, associated with gestational duration, 15 are associations stemming from maternal alleles and seven are associations stemming from maternal and baby alleles. Another pair of variants were associations stemming only from baby alleles.
These extraordinary findings, resulting from an analysis of 195,555 women for the gestational duration inquiry and more than 279,00 women for the preterm birth inquiry, were made possible through a partnership between Dr. Zhang’s PRC team and a group of European and international universities that provided biological samples on a scale simply impossible to replicate in the U.S. due to various factors, chief among them a more nascent system for systematically collecting pregnancy phenotype data and biospecimens for research.
The sheer size of the sample for the gestational duration analysis—a fourfold increase compared to the first, and until now, largest published maternal GWAS of gestational duration, led by Dr. Zhang in 2017—makes this study an incredibly reliable, insightful piece of genetics research on preterm birth that will serve as a pivotal foundation for further genetics research in the pregnancy space for years to come.
“In our first study, we saw these significant associations between genetic variants and gestational durations and preterm birth, and in this study, we’re confident to claim these associations,” Dr. Zhang said, “meaning that we know for a fact that there is a link, though perhaps not direct, between these specific variants and the length of labor and preterm birth.”
“That’s significant.”
Dr. Zhang’s next steps include validating the study’s findings in diverse populations (the majority of the current study participates were of European descent); studying the biological mechanisms of these associations to understand exactly how these variants influence gestational duration; and narrowing into the exact origins of the gestational duration and fetal birth weight phenomenon. For example, it’s unclear whether a single variant in mom and baby directly influences both gestational duration and fetal growth, or if there are actually multiple variants in the same genomic region in both mom and baby influencing each trait.
Dr. Zhang’s bigger goal, and he appreciates this is further down the line, is to use genomic information to predict the length of gestation so women at risk can be identified, interventions administered, and the worst preterm birth outcomes avoided.
“We know that genetics is the leading risk factor in preterm birth,” said Dr. Zhang. “Even though the identified genetic variants only explain 2.2% of the variance in gestational duration, that percentage is higher than any single known environmental risk factor.”
“This is why our team and collaborators are working hard to discover more of these genetic variants, hoping that in combination, these variants could be able to predict birth timing, which will be the ultimate discovery for moms and babies.”