Identifying Placental-Related Genes that Regulate Birthweight

The fetus is nestled upside down and colored orange, in a pregnant person’s body, which is colored blue. The placenta is shaded a darker orange at the top of the uterus.

Stock image of a developing fetus.

A fetus develops and grows in the womb for nearly 10 months, but the environment in which this occurs can set the stage for a person’s future health. For example, a baby’s birthweight can have long-term consequences—low birthweight affects survival during the newborn period, and high birthweight can elevate a person’s future risk for cardiovascular and metabolic diseases. This concept of “fetal programming” is not new, but scientists are still uncovering precisely how this happens.

In a study led by Fasil Tekola-Ayele, Ph.D., an Earl Stadtman Investigator in the Epidemiology Branch, researchers identified candidate genes that regulate birthweight via epigenetic and transcriptomic mechanisms in the human placenta. The team integrated genetic variants associated with birthweight in genome-wide association studies (GWAS) with placental methylation and gene expression information. Their analyses identify functional gene pathways in an important organ that is often excluded from tissue-specific gene expression resources.

The researchers discovered placental DNA methylation and gene expression targets for several birthweight GWAS loci. The target genes are broadly enriched in cardiometabolic, immune response, and hormonal pathways. The study team also found that methylation causally influences WNT3A, CTDNEP1, and RANBP2 expression in the human placenta, and they identify PLEKHA1, FES, CTDNEP1, and PRMT7 as likely functional effector genes. Follow-up studies, particularly those examining the maternal-placenta-fetal interface, can help identify therapeutic targets to improve fetal growth outcomes and future heath.

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