Genetic variants linked to placenta growth and to the health of the mother and child

Disease and treatment 21. dec 2023 4 min Senior Scientist Bjarke Feenstra Written by Kristian Sjøgren

The growth and development of the placenta is crucially important for healthy development of a fetus. Now researchers in a large international collaboration have discovered which genetic variants are most strongly associated with the growth and size of the placenta. A researcher behind the study says that this also provides new knowledge on the genetic component of complications in pregnancy.

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The placenta has a crucial influence on health in the first stages of life. It provides oxygen and nutrients to the developing fetus, helps the fetus get rid of waste products, and exchanges hormones and antibodies between the mother and the fetus. The placenta should therefore ideally be in good health.

Suboptimal placenta function can lead to adverse pregnancy outcomes, such as pre-eclampsia, fetal loss or fetal growth restriction.

Now a major new international study shows which genetic variants are associated with the growth of the placenta during pregnancy.

The discovery indicates that certain genetic variants can impede the growth of the placenta and adversely affect the fetus.

The insight provides more knowledge on the factors that control the development of the placenta and how this affects not only a child’s health at birth but also how the child’s health develops later on in life.

“Our results contribute to better mechanistic understanding of the interplay between health during fetal development and health for the rest of life. Some genes we know about from the development of diabetes are also associated with the growth of the placenta,” explains a leading researcher behind the study, Bjarke Feenstra, Senior Researcher and Group Leader at Rigshospitalet and Statens Serum Institut, Copenhagen.

The research has been published in Nature Genetics.

Placenta size affects health outcomes

The development of the placenta is well known to influence both how the pregnancy progresses and the health of the child.

For example, a placenta that is too small can lead to growth restriction and low birthweight, which is also associated with an increased risk of the child later developing various conditions, such as diabetes or attention-deficit/hyperactivity disorder.

Based on this, the researchers wanted to learn more about the genetic factors that are associated with the growth of the placenta.

“We wanted to understand causal relationships, the basic biology and what controls the growth of the placenta. This study is the first time we have collected enough data to be able to delve into these questions,” says Bjarke Feenstra.

Large volume of data

The researchers obtained data from many databases in Denmark, Norway, the United Kingdom and elsewhere.

The study included data on common genetic variants throughout the genome for mothers, fathers and children. Further data on the weight of the placenta at the time of birth, any pregnancy complications and the child’s birthweight were obtained from birth records.

The researchers collected data on 65,000 children, 60,000 mothers and 50,000 fathers and searched for genetic variants – locations in the genome, where the DNA differs slightly between people – that are associated with the growth of the placenta.

“We included data from very large cohorts in Denmark such as the Danish Blood Donor Study, the Danish National Birth Cohort and the Initiative for Integrative Psychiatric Research (iPSYCH) cohort, and we investigated about 10 million common genetic variants for each person,” explains Bjarke Feenstra.

Forty genes associated with the placental growth

The study identified 40 independent genetic variants associated with the growth of the placenta: 26 in the genome of the fetus and four in the mother’s genome.

Three genetic variants were associated regardless of whether they were in the mother’s or the child’s genome.

The researchers knew several of the gene variants from previous studies of birthweight, but 12 variants appeared to be associated only with the weight of the placenta.

According to Bjarke Feenstra, the fact that most of the associated genetic variants show their effect through the genome of the fetus is not surprising.

Once the egg is fertilised, it divides many times in rapid succession. After about five days, it attaches itself to the uterine wall, and what later becomes the placenta is formed from some of these first cells.

“Most of the placental cells originate in the fetus. Thus, it is not surprising that the genetic variants in the fetus have the strongest association with the growth of the placenta,” says Bjarke Feenstra.

Genes have different roles during fetal growth

The researchers examined the genes identified as being associated with placental growth. Some of the genetic variants associated with placental growth are also linked with an increased risk of pre-eclampsia of the type that occurs late in pregnancy.

“One potential explanation is that the placenta can grow a little too much and that the mother’s cardiovascular system may not be able to keep up, resulting in responses such as high blood pressure and late-onset pre-eclampsia,” explains Bjarke Feenstra.

Other identified genes are associated with the transport of antibodies from the mother to the child during fetal development and the shape and structure of the placenta. Animal experiments have previously shown that turning off these genes makes the placenta develop abnormally.

The researchers also identified genetic variants previously associated with elevated levels of blood glucose among mothers and increased insulin production in the fetus.

“We have obtained some clues about the mechanisms involved when the placenta does not develop optimally. Each of the identified genes must be followed up in later studies so that we can learn more about the exact roles they have,” says Bjarke Feenstra.

Investigating the activity of genes in placental tissue

The researchers will delve deeper into the data and expand the data with more studies.

Bjarke Feenstra is collaborating with colleagues at Statens Serum Institut on not just examining DNA but also how active each individual gene is in samples from placentas taken immediately after birth.

About half of these placenta samples are donated by mothers who experienced pre-eclampsia, and others are donated by mothers who did not experience pregnancy complications.

“Comparing our genetic findings about the growth of the placenta with the upcoming very detailed measurements in tissue samples from this fascinating organ will be very interesting. Overall, this will provide new knowledge about the mechanisms of pre-eclampsia. In addition, we are making the aggregated genetic results for all 10 million genetic variants from our placenta weight study available so that other researchers interested in this field can delve into them and examine them with other approaches,” concludes Bjarke Feenstra.

Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth” has been published in Nature Genetics. Bjarke Feenstra was partly funded by the Novo Nordisk Foundation and several of the other authors are affiliated with the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, which is partly funded by the Foundation.

Bjarke Feenstra is a senior scientist and research group leader at Statens Serum Institut and Copenhagen University Hospital, Rigshospitalet. He has a...

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