Common gene variants can influence risk of rare neurodevelopmental conditions

Common genetic variants, including some linked to risk of developing schizophrenia and depression in later life, are linked to the risk of rare neurodevelopmental conditions in children.

Researchers from the Wellcome Sanger Institute near Cambridge and collaborators looked at genomic data from thousands of children with rare neurodevelopmental conditions, and their parents, to investigate if genetic variants influence the chance of having such a condition. They found that variants that are common in people of British ancestry can explain close to ten percent of the chance of having a developmental disorder. These differences contributed less to the risk of neurodevelopmental conditions in the 36 percent of children studied who had a diagnosis of a monogenic condition, but more to the risk in children without a diagnosis.

'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,' said senior author Dr Hilary Martin of the paper published in Nature.

Genetic variants that are common (present in more than one out of 100 people) often have very little impact on human diseases or traits on their own. However, a single genome carries millions of them – this is known as the 'polygenic background', and the degree to which it can influence monogenic traits is unclear.

The researchers used genomic data from two UK-based projects to compare the genomes of more than 11,500 people who had a rare developmental condition to 9100 of their parents and 26,800 people who did not. They confirmed that common variants only account to about ten percent of the risk of a developmental condition, as they had previously estimated in a smaller 2018 study published in Nature.

They also found that variants linked to psychiatric conditions including schizophrenia were also common in children who had rare neurodevelopmental disorders – suggestive of common biological mechanisms between them. Conversely, genetic variants previously linked to spending fewer years in education were found to underpin the common genetic variability shared between other neurodevelopmental disorders and mental health conditions such as depression and attention-deficit hyperactivity disorder.

There were more of these common variants in patients without a single causing gene mutation than in those who had this genetic diagnosis. This supports the 'liability threshold model' theory which predicts that, if a person is diagnosed without a large-effect variant, such as a known monogenic disorder, then more common and rare variants that modify the risk, and possibly environmental factors, must had been present.

Lastly, the researchers found that the presence of such variants in the parents influences the risk of the child developing a condition, even when the variant was not present in the genome of the child. They hypothesised that one of the reasons for this could be genetic variants linked to premature birth, which is in turn linked to increased risk of neurodevelopmental disorder, but authors stated future work need to be done to better understand this finding.