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Broad spectrum of autism depends on spectrum of genetic factors

Newswise – Autism Spectrum Disorder (ASD) is referred to as the “spectrum” because the clinical features of ASD range from mild social impairments in some people to severe intellectual disability or epilepsy in others. Genetic studies have offered clues, identifying genes associated with ASD, but despite finding many pieces of the puzzle, scientists have yet to figure out exactly how they all fit together, and why ASD has such a wide range of symptoms. Why is there a difference?

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, reports significant progress in understanding how the combined effects of a rare mutation and common genetic variation determine whether a child will develop ASD.

“We know that the genetics of autism is complex, but we didn’t really have a picture of how the genetic inheritance of rare and common variants works in families,” said senior study author Jonathan Sebut, PhD, professor and head of Bayester’s Said the 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 individuals from 11,213 families in which at least one member (child or parent) had been diagnosed with ASD. The goal was to determine how combinations of genetic factors contribute to risk and clinical 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 forms that are inherited from parents; and polygenic scores that measure the genetic load of common forms of small effect.

“When you add up all the key factors that we can detect in the genome,” Sebat said, “the predicted value of DNA sequencing more than doubles when you test only one category at a time.” Combining rare gene mutations with a polygenic score has the potential to make genetic testing more accurate.”

Sex is another major factor that affects the risk of autism. ASD is diagnosed in men at a ratio of 4 to 1 compared to women. In the new study, the authors show that the lower prevalence of ASD in women is due to a “female protective effect” in which women have a greater tolerance for genetic risk than men. They found that children with ASD and their typically developing siblings had a higher total genetic load on average in women than in men. “Both the rare variant and the polygenic score show evidence of a ‘female protective effect’,” said Sebat, “that suggests that the ‘liability threshold’ for autism varies by sex, with women having a higher threshold than men.” “

The researchers also looked at the effects of genetic factors on a variety of behaviors, including social communication, repetitive behaviors, and motor coordination. They found that genetic factors influenced the severity of symptoms in children with ASD and their typically developing siblings and parents. They also found that different factors were 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 spectrum of symptom severity in ASD is due to a spectrum of genetic risk,” Sebat said. “People who meet the diagnostic criteria for autism may be at an extreme, but these types of risk factors are present in all of us to varying degrees. We all have a continuum somewhere. are on.”

Finally, the authors found that different genetic factors lead to different patterns of gene expression in the developing brain. Genes implicated by rare variants were strongly enriched in embryonic brain neurons. In contrast, genes implicated by common variants were more widely expressed and were not dramatically enriched in specific cell types. These differences in brain expression may partly explain their association with different traits.

Taken all together, the authors wrote, the different parts of the autism spectrum are due to each individual having a unique combination of genetic factors.

Co-authors include: Danny Antaki, James Guevara, Adam X. Maihofer, MaryKe Klein, Madhusudan Gujral, Onh Hong, Alison R. Muotri, Lilia M. Iacocheva, Eric Courchesne, Karen Pierce, Joseph G. Gleason and Caroline M. Nivergelt, all at UC San Diego; Jacob Grove, Aarhus University, Denmark; Caitlin E. Carey and Alice Robinson, Harvard University; Maria J. Arrange, Mutual Teaching and Research Foundation, Spain; Amaya Harvas, Terasa Mutual University Hospital, Spain; Christina Corsello at the University of North Carolina; and Keith Vox, Human Longevity Inc.

This research was supported, in part, by SFARI (grant SFARI 606768), the National Institutes of Health (grant MH113715, MH119746, 1MH109501, MH106595, GM008666), the Escher Fund for Autism (grant 20171603) and the Dutch Research Council (grant NWO 45219212 ).

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