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Summary: Genetic factors influence the severity of symptoms in children on the autism spectrum, and different genetic factors have been linked to different symptoms of ASD.
Source: UCSD
Autism Spectrum Disorder (ASD) is called “spectrum” because the clinical features of ASD range from mild social impairment in some people to severe intellectual disability or epilepsy in others.
Genetic studies have provided clues and identified genes associated with ASD, but while scientists have found many pieces of the puzzle, they have yet to figure out how they all fit together and why there are such huge differences in ASD symptoms.
In a new study published in the June 2, 2022 online edition of natural geneticsan international team of scientists led by researchers from the University of California San Diego School of Medicine, reports significant advances in understanding how the combined effects of rare mutations and common genetic variations determine whether a child will develop ASD.
“We knew that the genetics of autism are complex, but we didn’t really have a picture of how genetic inheritance of rare and common variants works in families,” said lead study author Jonathan Sebat, Ph.D., professor and director of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases at the UC San Diego School of Medicine.
In the latest study, Sebat’s team analyzed the genomes of 37,375 people from 11,213 families in which at least one member (child or parent) had been diagnosed with ASD. The aim was to determine how combinations of genetic factors contribute to risk and clinical symptoms.
Researchers looked at a variety of factors, such as: B. de novo mutations, which are new genetic changes that appear in a child for the first time; rare variants inherited from parents; and polygenic scores, which quantify the genetic burden of common low-impact variants.
“If you combine all the important factors that we can detect in a genome,” Sebat said, “the predictive value of DNA sequencing doubles compared to testing just one category at a time.” Combining rare gene mutations with polygenic scores has the potential to make genetic testing more accurate.”
Sex is another important factor affecting autism risk. Males are diagnosed with ASD in a 4 to 1 ratio compared to females. In the new study, the authors showed that the lower prevalence of ASD in women is partly due to a “female protective effect,” in which women have a greater tolerance to genetic risk than men.
They found that the overall genetic burden was greater, on average, in women than in men, both in children with ASD and in their typically developing siblings.
“Both rare variants and polygenic scores show evidence of a ‘female protective effect,'” Sebat said. “This suggests that the ‘liability threshold’ for autism differs by gender, with females having a higher threshold than males.”
Researchers also looked at the impact of genetic factors on a variety of behaviors, including social communication, repetitive behavior and motor coordination. They found that genetic factors influenced the severity of symptoms in children with ASD and in their typically developing siblings and parents.
They also found that different factors were linked to different symptoms. Rare variants and polygenic scores had an impact on social communication, but only rare variants had an impact on motor coordination.
“The spectrum of symptom severity in ASD is due to a spectrum of genetic risks,” Sebat said. “People who meet the diagnostic criteria for autism may be an extreme, but these types of risk factors are present in all of us to varying degrees. We are all on a continuum somewhere.”
Finally, the authors found that different genetic factors have different patterns of gene expression in the developing brain.
Genes affected by rare variants have been highly enriched in neurons of the fetal brain. In contrast, genes involved in common variants were more widely expressed and not dramatically enriched in certain cell types. These differences in brain expression may partially explain their associations with different traits.
Overall, the authors wrote, the different parts of the autism spectrum are due to each individual having their own unique combination of genetic factors.
About this news from genetics and autism research
Author: Scott LaFee
Source: UCSD
Contact: Scott LaFee-UCSD
Picture: The image is in the public domain
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Original research: Closed access.
“A phenotypic spectrum of autism is due to the combined effects of rare variants, polygenic risk, and sex” by Danny Antaki et al. natural genetics
abstract
A phenotypic spectrum of autism is due to the combined effects of rare variants, polygenic risk, and sex
The genetic etiology of autism spectrum disorder (ASD) is multifactorial, but how combinations of genetic factors determine risk is unclear.
In a large family sample, we show that genetic burdens are inversely correlated with rare and polygenic risk in cases and are greater in females than in males, consistent with a liability threshold that differs by sex.
De novo mutations (DNMs), rare inherited variants, and polygenic scores were associated with different dimensions of symptom severity in children and parents.
The effects of parental age on offspring ASD risk were attributed to a combination of genetic mechanisms, including DNMs accumulating in the paternal germline, and inherited risk affecting parental behavior.
Genes involved in rare variants were enriched in excitatory and inhibitory neurons compared to genes involved in common variants.
Our results suggest that a phenotypic spectrum of ASD is attributable to a spectrum of genetic factors affecting different neurodevelopmental processes.
