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New Genetic Loci Linked to Preterm Birth, Pregnancy Length

NEW YORK (GenomeWeb) – A team led by scientists at Cincinnati Children's Hospital Medical Center and the Norwegian Institute of Public Health has identified half a dozen genomic loci linked to gestational duration or preterm birth risk.

As they reported in the New England Journal of Medicine yesterday, the researchers conducted a genome-wide association study involving nearly 44,000 women participating in 23andMe research, searching for variants associated with gestational duration or birth before 37 weeks of pregnancy. Their search led to six loci with significant ties to gestational duration in the discovery group and in thousands more women, including three loci that were also associated with preterm birth.

"Previous research has suggested that about 30 to 40 percent of the risk for preterm birth is linked to genetic factors," co-senior author Louis Muglia, co-director of Cincinnati Children's Hospital's Perinatal Institute and a researcher with the March of Dimes Prematurity Research Center Ohio Collaborative, said in a statement. "This new study is the first to provide robust information as to what some of those genetic factors actually are."

For the discovery stage of the GWAS, Muglia and colleagues focused on 43,568 women of European ancestry who are customers of 23andMe and had completed surveys through the company's research program, including 3,331 women who gave birth before 37 weeks of gestation. Another 2,434 women had late births, while 37,803 reported giving birth at term (between 37 and 42 weeks of gestation).

When the team considered the individuals' patterns at more than 15.6 million SNPs, it narrowed in on variants at nine loci with potential ties to gestational duration, two loci that appeared to be associated with preterm birth, and three loci that seemed to be linked to both traits.

In a replication analysis involving 8,643 more women and 4,090 infants from several Nordic birth studies, the investigators replicated associations at six loci — in and around the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C genes. Of those, the variants neighboring EBF1, EEFSEC, and AGTR2 appeared to contribute to both preterm birth and gestational duration in general, they reported.

From there, the team delved into the SNPs in more detail. When infant samples were available, for example, the researchers looked at the role that infant genotype might play in preterm birth and gestation. They also used RNA sequencing to uncover variant-related differences in WNT4 binding by estrogen receptor 1 in endometrial tissues or cell lines.

"With this foundation, we anticipate that larger studies of samples with maternal and fetal genotyping associated with data regarding gestational duration will further refine our understanding of human pregnancy and the risk of adverse pregnancy outcomes," the authors concluded.