Predictive gene expression model finds that some factors involved in lifelong metabolism are evident in utero.

Weight, body mass index (BMI) and obesity status early in life have been shown to indicate risk for adult BMI and obesity. Birthweight has also been associated with adult BMI and obesity, but the mechanisms affecting these traits and their association remain unclear.

A recent study at Vanderbilt University Medical Center published in Scientific Reports found evidence that genetically predicted placental expression of specific genes is associated with birthweight and adult BMI.

“This study suggests that the process leading to birthweight and adult BMI that begins with genetic factors has intermediate steps that occur as early as the placenta,” said Elizabeth Jasper, Ph.D., an assistant professor of obstetrics and gynecology and lead author of the study.

“It supports the developmental origins of health and disease hypothesis that biological and metabolic processes that occur in utero shape a baby’s health long term.”

A fellow in the Vanderbilt Genomic Medicine Training Program when the research began, Jasper worked alongside senior author Digna R. Velez Edwards, Ph.D., director of the Division of Quantitative Sciences in the Department of Obstetrics and Gynecology, and Todd L. Edwards, Ph.D., a Vanderbilt geneticist, whose NIH-funded lab helped to develop a novel placenta model for genetically predicted gene expression that was used in the study.

“We already know there are number of things at play – nutrition, stress, environmental toxins, preexisting disease – that impact these phenotypes,” Jasper explained. “We’re exploring the baseline genetics.”

“The process leading to birthweight and adult BMI has intermediate steps that occur as early as the placenta.”

Expanding the Scope

In the Vanderbilt study, summary data from multiple large-scale genome-wide association studies (GWAS) were evaluated with the placenta model. Data on neonatal factors, including birthweight, came from GWAS summary statistics from the Early Growth Genetics (EGG) consortium (298,142 individuals). Adult BMI summary statistics came from the Genetic Investigation of Anthropometric Traits consortium – up to 681,275 individuals.

“Initially, we were going to look at a small cohort, but with the availability of the EGG data we broadened our scope,” Jasper said. “For both phenotypes, we found genes that were associated with birthweight and BMI, and we validated some single nucleotide polymorphisms we’d found before.”

Predicted gene expression of 24 genes was significantly associated with birthweight and 182 with BMI in placenta tissue. However, placental expression of only 15 of the genes associated with birthweight and 110 of those associated with BMI were significantly and exclusively associated with these outcomes.

“We found a larger number of genes where placental expression was associated with BMI. The biological processes and molecular functions of the genes varied widely,” Jasper said.

Gene expression of ADCY5 was significantly associated with birthweight in the placenta. It has been consistently associated with birthweight and Type 2 diabetes, a phenotype closely linked to increasing BMI, as well as energy storage, metabolism and homeostasis.

“This was another clue that we’re on the right track because these factors are tied in with development of pancreatic beta cells,” Jasper said.

Ongoing Research

Jasper says the data used to build the placenta model derived from published data on pregnancies and births but excluded maternal genetic factors. The investigators, led by Velez Edwards, are now collecting both placentas and maternal data at Vanderbilt to study correlation between fetal and maternal genotypes and compare results between them.

The team will use another model to evaluate placentas from extremely preterm infants, under 28 weeks.

“This is something else that could be at play: if how far along you are in pregnancy affects these traits,” Jasper said.

The investigators are also conducting follow-up studies of BMI at other points in time – not just at birth or in adulthood, but throughout childhood, Jasper said.

“Does the strength of the association decrease as you age or is it still there when you’re 10 or through puberty when things are different?”

Later, they will study environmental influences during pregnancy that may impact birthweight and BMI.

“We’re far off from this being able to affect care, but it adds more proof to what we already know,” Jasper said. “It helps us to identify the pathways that are involved in birthweight and BMI.”

If lifestyle-related disease is formed by the interrelation between genes and the environment, she added, these studies that identify genes and tissue context may provide biomarkers or drug targets that could help predict or prevent adverse outcomes.

Bios

Elizabeth Jasper, Ph.D.

Elizabeth Jasper, Ph.D., is an assistant professor of obstetrics and gynecology at Vanderbilt University Medical Center. She recently completed a bioinformatics fellowship in the Vanderbilt Genomic Medicine Training Program.