New study links common DNA differences to unexplained rare neurological disorders

The combination of common DNA differences may help explain why some people have a rare neurological brain disorder without a specific, single genetic mutation causing it.

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

The study, published in Natureexpanded a 2018 study by the same group, which found that while their overall role is small, common genetic differences may help explain why some people have a neurodevelopmental disorder. In particular, these common DNA differences overlap with those more likely to be found in people suffering from later-onset conditions such as depression and schizophrenia.

Furthermore, this new study found that common genetic differences, if present in the parents, can influence the likelihood of their child developing a neurodevelopmental disorder, even if the child does not directly inherit those 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 can work together to cause neurodevelopmental disorders. In the longer term, these findings could help families and doctors better understand, diagnose and treat these conditions, and predict the likelihood of parents having a second affected child.

Rare neurodevelopmental disorders, which affect less than 1 percent of people, affect brain growth and development in childhood and can lead to learning problems and other conditions such as small head or seizures.

In about half of people with neurodevelopmental disorders, the cause is a single, 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, also called a variant, it is known as a genetic diagnosis.

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

In some cases, there may not be any genetic mutation behind the condition. Instead, it could be a complex interplay between different types of genetic and environmental factors. Gaining a better understanding of all the factors involved, including the role of common genetic differences, can give you 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, including people with neurodevelopmental disorders and their parents4, plus thousands of people without rare brain disorders. This produced a combined data set of more than 40,000 people in Great Britain.

The researchers found that people with neurodevelopmental disorders, but without a genetic diagnosis, have a greater number of common DNA differences linked to impaired cognitive skills and later-onset brain disorders than people with a genetic diagnosis. The findings support a 'liability threshold model', whereby several types of DNA differences, both rare and common, in addition to environmental factors, jointly contribute to the risk of developing neurodevelopmental disorders.

This study estimates that common DNA differences together account for about 10 percent of the reason why some people develop a neurodevelopmental disorder and others do not. Overall, several common DNA differences have only a small effect on the likelihood of developing a rare neurological disorder 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 later develop mental health problems such as depression and schizophrenia, informing researchers about the interplay between genetics and mental health.

Some DNA differences also appeared to be more common in people who get lower scores on tests of mental processes, including memory and problem-solving skills, and who spend less time in formal education. However, researchers show that the DNA differences associated with cognitive test scores and education do not directly affect a child's chance of developing a neurodevelopmental disorder.

“Our research suggests that common inherited DNA differences associated with rare neurological disorders also overlap with those associated with later-stage health problems. This insight broadens our understanding of how genetics influences a range of health outcomes,” says Dr. Emilie Wigdor, co-researcher. first author formerly at the Wellcome Sanger Institute, now at the University of Oxford.

“We found that common DNA differences in parents, even if not passed on to their child, could still influence the child's risk of developing a rare neurodevelopmental disorder, although this needs to be addressed in the future.” confirmed with new data sets and methods. 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 from the Wellcome Sanger Institute.

“As they prepared to publish these results, the research team was keen to include feedback from parents whose children have neurodevelopmental disorders. Some of the issues explored in this article are sensitive and may be challenging for families to hear ; we were able to advise on how best to explain the findings to people who share our experiences.

“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 participant panel at Genomics England.

“It is important that we understand the cause of neurodevelopmental disorders in all patients, not just those with a clear diagnosis of one gene. Although we 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 DNA differences work together to cause them.

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