New study links common DNA differences to rare, unexplained neurodevelopmental conditions

The combination of common differences in DNA may help explain why some people suffer from a rare neurodevelopmental brain disease without a specific, unique genetic mutation causing it.

Researchers at the Wellcome Sanger Institute and their collaborators examined data from thousands of children with rare neurodevelopmental diseases and their parents to study how common DNA differences contribute to these conditions.

The study, published in Natureextended a 2018 study by the same group showing that although their overall role is small, common genetic differences may help explain why some people suffer from neurodevelopmental disease. Specifically, these common differences in DNA overlap with those that are more likely to be found in people affected by late-onset illnesses, such as depression and schizophrenia.

Additionally, this new study found that common genetic differences, when present in parents, can affect their child’s risk of developing a neurodevelopmental disease, even if the child does not directly inherit these genetic differences. However, more research is needed to fully understand this.

Overall, this study brings us closer to understanding how different genetic and environmental factors may act together to cause neurodevelopmental disorders. In the longer term, these results could help families and doctors better understand, diagnose and manage these conditions, and predict the risk of parents having a second affected child.

Rare neurodevelopmental conditions, those seen in less than 1 percent of people, affect brain growth and development during childhood and can lead to learning difficulties and other conditions such as small head size or convulsions.

In about half of people with neurodevelopmental disorders, the cause is a unique, rare DNA change in one or both copies of a gene that plays an essential role in brain development. If researchers can identify the genetic change, sometimes called a variant, it is called a genetic diagnosis.

Many patients with rare neurodevelopmental diseases currently do not have a genetic diagnosis, and ongoing research studies such as the 100,000 Genomes Project and the Deciphering Developmental Disorders (DDD) study are attempting to change this and understand new other causes of these conditions.

In some cases, there may not be a single genetic mutation causing the disease. Rather, it could be a complex interaction between different types of genetic and environmental factors. Better understanding all the factors involved, including the role of common genetic differences, can help provide a more informed view of why these conditions develop.

In this study, Wellcome Sanger Institute researchers and collaborators analyzed data from the DDD Study and the 100,000 Genomes Project, which include people with neurodevelopmental diseases and their parents,4 as well as thousands of people without diseases rare brain diseases. This resulted in a combined dataset of over 40,000 people based in the UK.

Researchers found that people with neurodevelopmental disorders, but without a genetic diagnosis, had a higher number of common DNA differences associated with reduced cognitive ability and later-onset brain diseases than those with a genetic diagnosis. The findings support a “threshold model” in which different types of DNA differences, both rare and common, in addition to environmental factors collectively contribute to the risk of developing neurodevelopmental conditions.

This study estimates that common differences in DNA cumulatively explain about 10% of the reasons why some people develop a neurodevelopmental disease but others do not. Overall, multiple common differences in DNA have only a small effect on the risk of developing a rare neurodevelopmental disease and cannot be used to accurately predict who might be affected.

These common differences in DNA overlap with those seen in people who develop late-onset mental health problems, such as depression and schizophrenia, helping to inform researchers about the interplay between genetics and mental health. .

Some DNA differences have also been found to be more common in people who score lower on tests of mental processes, including memory and problem-solving skills, and who spend less time in formal education. However, researchers show that DNA differences linked to cognitive test scores and education do not directly affect a child’s risk of developing a neurodevelopmental disease.

“Our research suggests that common inherited DNA differences associated with rare neurodevelopmental diseases also overlap with those linked to later-stage health problems. This information expands our understanding of how genetics influence a range of health outcomes,” said Dr Emilie Wigdor, co-first author previously at the Wellcome Sanger Institute, now at the University of Oxford.

“We found that common DNA differences in parents, even when not passed on to their child, could still influence the child’s risk of developing a rare neurodevelopmental disease, although this needs to be confirmed at “If confirmed, future research could explore how these effects are influenced by family environment and other relevant risk factors,” said Dr. Qinqin Huang. , co-first author of Wellcome Sanger Institute.

“As they prepared to release these findings, the study team wanted to incorporate feedback from parents whose children have neurodevelopmental issues. Some of the issues explored in this article are sensitive and may be difficult for families; we were able to give advice on how best to explain the results to people who share our lived experience.

“I am grateful to the team for this opportunity, which I believe has been beneficial to both the researchers and the patient community, and I hope that such collaborations become more common in the future,” said Jillian Hastings Ward, MBE, patient representative and former Chair of the Genomics England Participant Panel.

“It is important that we understand the cause of neurodevelopmental disorders in all patients, not just those with a clear monogenic diagnosis. Although we have found that common DNA differences play only a small role in the development of these conditions, this study provides a more informed view of how different types of differences in DNA interact to cause them.

“In the future, research into this could potentially help give families more information about their chances of having another affected child, and could potentially help inform strategies to improve outcomes for children. This research also highlights how large-scale genetic research can yield new insights and we are extremely grateful to the families for their participation and commitment because without them this research would not be possible,” said Dr Hilary Martin , lead author from the Wellcome Sanger Institute.