The combination of common DNA differences can help explain why some people have a rare neurodevelopmental brain condition without a specific, single genetic mutation causing it.
Researchers from the Wellcome Sanger Institute and collaborators looked at data from thousands of children with rare neurodevelopmental conditions and their parents to investigate how common DNA differences contribute to these conditions.
The study, published in Nature, extended a 2018 study by the same group showing that while their overall role is small, common genetic differences can help to explain why some people have a neurodevelopmental condition. Specifically, these common DNA differences overlap with those that are more likely to be found in people affected by later-onset conditions, such as depression and schizophrenia.
In addition, this new study found that common genetic differences, when present in the parents, may affect the chance of their child developing a neurodevelopmental condition, even if the child does not inherit those genetic differences directly. However, more research is needed to fully understand this.
Overall, this study brings us closer to understanding how different genetic and environmental factors may work together to cause neurodevelopmental conditions. In the longer term, these findings may help families and doctors to better understand, diagnose, and manage these conditions, and predict the chance of parents having a second affected child.
Rare neurodevelopmental conditions, those seen in less than 1 percent of people, affect the growth and development of the brain in childhood and can lead to learning difficulties and other conditions such as small head size or seizures.
In about half of people with neurodevelopment conditions, the cause is a single, rare DNA change in either 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 known as a genetic diagnosis.
Many patients with rare neurodevelopmental conditions currently do not have a genetic diagnosis, and there are ongoing research studies such as the 100,000 Genomes Project and the Deciphering Developmental Disorders (DDD) study that are trying to change this and to understand other causes of these conditions.
In some cases, there might not be a single genetic mutation behind the condition. Instead, it could be a complex interplay between different types of genetic and environmental factors. Understanding more about all the factors involved, including the role of common genetic differences, can help give a more informed view of why these conditions develop.
In this study, researchers from the Wellcome Sanger Institute and collaborators analyzed data from the DDD study and the 100,000 Genomes Project, which include those with neurodevelopmental conditions and their parents,4 plus thousands of people without rare brain conditions. This gave a combined data set of over 40,000 people based in the UK.
The researchers found that those with neurodevelopmental conditions, but no genetic diagnosis, have a higher number of common DNA differences associated with reduced cognitive ability and later-onset brain conditions than those with a genetic diagnosis. The findings support a "liability threshold model" here 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 DNA differences accumulatively account for about 10 percent of why some people develop a neurodevelopmental condition but others do not. Overall, multiple common DNA differences only have a small effect on the chance of developing a rare neurodevelopmental condition and cannot be used to accurately predict who might be affected.
These common DNA differences were found to overlap with those seen in people who go on to develop later-onset mental health conditions, such as depression and schizophrenia, helping to inform researchers on the interplay between genetics and mental health.
Some DNA differences were also found to be more common in people who get lower scores in tests of mental processes, including memory and problem-solving abilities, and spend less time in formal education. However, researchers show that the DNA differences linked to cognitive test scores and education do not directly affect a child's chance of developing a neurodevelopmental condition.
"Our research suggests that common inherited DNA differences associated with rare neurodevelopmental conditions also overlap with those linked to later-stage health conditions. This insight broadens 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 transmitted to their child, might still influence the child's risk of developing a rare neurodevelopmental condition, although this needs to be confirmed in future with new datasets and methods. If confirmed, future research could explore how these effects are influenced by the familial environment and other relevant risk factors," said Dr. Qinqin Huang, co-first author from the Wellcome Sanger Institute.
"As they were preparing to publish these results, the study team were keen to incorporate feedback from parents whose children have neurodevelopmental conditions. Some of the issues explored in this paper are sensitive and have the potential to be challenging for families to hear; we were able to advise on how best to explain the findings to people who share our lived experience.
"I am grateful to the team for this opportunity, which I believe has been beneficial to the researchers and the patient community alike, and I hope that such collaborations become more commonplace in the future," said Jillian Hastings Ward, MBE, patient representative and former Chair of the Participant Panel at Genomics England.
"It's important that we understand the cause of neurodevelopmental conditions in all patients, not only those with a clear-cut single-gene diagnosis. While we found that common DNA differences only play a small role in the development of these conditions, this study gives a more informed view of how different types of DNA differences work together to cause them.
"In the future, research on this may ultimately help give families more information about their chance of having another affected child, and could possibly help inform strategies to improve children's outcomes. This research also highlights how large-scale genetic research can give new insights and we are extremely grateful to families for their participation and engagement as without them, this research would not be possible," said Dr. Hilary Martin, senior author from the Wellcome Sanger Institute.