Autism spectrum disorder (ASD) is referred to as a “spectrum” because the clinical features of autism spectrum disorder range from mild social impairments in some people to severe intellectual disability or epilepsy in others. Genetic studies have provided clues, identifying genes linked to autism, but although many pieces of the puzzle have been found, scientists have yet to discover how they all fit together, and why there is such a wide variation in ASD symptoms.
In a new study published in the June 2, 2022 online issue of nature geneticsAn international team of scientists, led by researchers at the University of California San Diego School of Medicine, has reported major advances in understanding how the combined effects of rare mutations and common genetic variation determine whether a child will develop autism.
We knew the genes for autism are complex, but we didn’t really have a picture of how the genetic inheritance of rare and common variants in families works.”
Jonathan Spatt, PhD, senior study author, professor and chair of the Bester Molecular Genomic Center for Neuropsychiatric Diseases at UCSD School of Medicine
In the latest study, Hibernate’s team analyzed the genomes of 37,375 individuals from 11,213 families in which at least one member (a child or parent) had been diagnosed with autism spectrum disorder. The aim was to determine how the combination of genetic factors contributes to clinical risk and symptoms. The researchers looked at a variety of factors, such as again Mutations, which are new genetic changes that occur for the first time in a child; rare variants inherited from parents; and polygenic scores that determine the genetic load of common variants of small effect.
“When you combine all the key factors we can detect in the genome, the predictive value of DNA sequencing is more than double compared to when you test just one category,” Spatt said. “The potential to make genetic testing more accurate.”
Gender is another major factor affecting autism risk. Males are diagnosed with autism 4 to 1 compared to females. In the new study, the authors show that the lower prevalence of autism spectrum disorder in females is due in part to the “female protective effect” in which females have a greater tolerance to genetic risk than males. They found that the overall genetic load was greater on average in females than in males, both in children with autism and in their normally growing siblings. “Both the rare variants and polygenic scores show evidence of a ‘female protective effect,'” Spatt said, indicating that the ‘responsibility threshold’ for autism varies with sex with females having a higher threshold than males. “
The researchers also looked at the effects of genetic factors on a variety of behaviours, including social communication, repetitive behaviors, and motor coordination. They found that genetic factors influenced the severity of symptoms in children with autism and in their typically developing siblings and parents. They also found that different factors are associated with different symptoms. Rare variants and polygenic scores had an effect on social communication, but only rare variants had an effect on motor coordination.
“The severity of autism spectrum disorder symptoms is attributable to a spectrum of genetic risk,” Spatt said. “People who meet the diagnostic criteria for autism may be extreme, but these types of risk factors are present to varying degrees in all of us. We are all somewhere in a continuum.”
Finally, the authors found that different genetic factors have different patterns of gene expression in the developing brain. Genes implicated by rare variants were strongly enriched in neurons in the fetal brain. In contrast, genes implicated by common variants were more widely expressed and not significantly enriched in specific cell types. These differences in brain expression may partly explain their associations with different traits.
The authors write that the different parts of the autism spectrum are attributed to the fact that each individual has a unique set of genetic factors.