Babies who are especially small or large at birth have not only a higher risk of complications at birth but also a greater risk of overweight, type 2 diabetes and high blood pressure in adulthood. Using a new revolutionary genetic method, researchers have succeeded in understanding how much the genes of a child and mother and the environment in the womb determine a child’s birth weight. According to the researchers, the new method can potentially help the parents of children at risk in giving their children a better start to a long and happy life.
Children inherit half their genes from their mother and half from their father. This genetic mix creates the unique characteristics of a child – both positive and negative. Some children have genes that limit their early growth or increase it more than normal. These metabolic effects can last their whole life. Helping children early in life can potentially give them a healthier and longer life. However, understanding the relationship between birth weight and health risks requires understanding and being able to distinguish between the genetic and environmental causes.
“The new method can separate these effects for the first time. Three quarters of the genetic effects on birth weight originate from the child’s genes; maternal genes, which also affect the environment in the womb, account for one quarter. This new method will potentially enable us to screen the children and parents so that we can help prevent lifestyle-related diseases at an early stage in life,” explains Jens-Christian Holm, Clinical Research Associate Professor, Department of Clinical Medicine, University of Copenhagen and consultant, Department of Paediatrics, University Hospital Holbæk.
New pieces of the puzzle
The researchers in this large international research project compared the genetic information of more than 300,000 mothers and the birth weight of one of their children. Using new statistical methods, the researchers successfully separated the effects of the genes of the mother and the fetus on the birth weight of the newborn infants. The research involved more than 200 international clinics from 20 countries participating in the Early Growth Genetics Consortium or the UK Biobank study.
“We conclude that the direct effects of a baby’s genes are the most important factor influencing birth weight. However, the mother’s genes that were not passed on to the baby provide about one quarter of the genetic effects. These genes affect the growth of the fetus by influencing the environment in the womb during pregnancy, including the amount of glucose supplied, which directly determines how much the fetus grows.”
In addition to determining the ratio between the effects caused by the genes of the fetus and the mother, the research also identified 190 independent association signals, of which 129 are new. This means that the researchers have obtained numerous new pieces of the puzzle that can help explain the relationships between genes and birth weight.
“These 190 association signals can potentially also be used to screen children for their risk of metabolic disorders, and if we can also understand the specific effects of the genes, we can help the children so that they can, for example, eat in a certain way and avoid becoming overweight. Further, understanding the mother’s genes may enable us to stabilize her glucose metabolism, which strongly affects the environment in the womb. The perspectives are really striking.”
Interestingly, the researchers also found numerous association signals involving both the genes of the mother and child. They sometimes reinforced each other and sometimes opposed each other.
“For example, some genetic effects raise the mother’s blood glucose, making the baby bigger because the fetus produces more insulin in response. However, if the child inherits the same genetic variants, this reduces the amount of insulin the child produces, limiting growth and counteracting some of the mother’s growth-promoting effects.”
A completely new way of thinking
The study is the largest of its kind so far and results in new insight into the complexities of how the genes of mothers and babies interact and affect birth weight. In addition, the study adds a new chapter to a previous study published in Nature in 2016, in which the researchers helped to identify 60 genes that influence birth weight, type 2 diabetes and cardiovascular diseases.
“In December 2018, we published a study from University Hospital Holbæk involving 920 overweight children whom we screened for combinations of 15 relatively frequent genes linked to overweight among children to determine whether our treatment is effective. The good news was that, no matter which or how many of these 15 common genes they had, we could help them lose weight and reduce their previous signs of metabolic disorders.”
Evidence indicates that a child’s genetics primes them to absorb too much or too little energy. By understanding the factors that affect birth weight among babies born very large or very small, Jens-Christian Holm hopes that we will be able to reduce children’s risk of obesity and its complications later in life.
“This is a completely new way of thinking, and the potential presents new perspectives. A new type of precision medicine that enables us to advise parents and children early. This could mean that some children need to be especially physically active or that the parents must pay special attention, for example, to sugar and fat given the genetic challenges the children face.”
Jens-Christian Holm understands the ethical implications of screening children based on their genes, but not screening them also has ethical implications if the children can otherwise be helped to live a longer and healthier life.
”There are naturally pitfalls in this, so we must thoroughly discuss both the technical issues of false positives and false negatives if we can identify a high-risk group but also the ethical aspects. However, I think this cuts both ways, and we owe future generations to seriously discuss the opportunities.”
”Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors” has been published in Nature Genetics. Several of the researchers are affiliated with the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen and with Steno Diabetes Center Copenhagen, which the Novo Nordisk Foundation also supports.