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The world’s largest whole-genome sequencing study of autism reveals 134 genes associated with autism

The world’s largest whole-genome sequencing study of autism reveals 134 genes associated with autism

The world’s largest whole-genome sequencing study of autism reveals 134 genes associated with autism

Summary: The researchers identified 134 genes associated with autism and a number of genetic changes associated with ASD. Notably, the study identified changes in copy number variations with likely associations with ASD, including autism-related variants in 14% of people on the autism spectrum.

Source: Hospital for sick children

Researchers at the Hospital for Sick Children (SickKids) have discovered new genes and genetic changes associated with autism spectrum disorder (ASD) in the largest whole-genome sequencing analysis of autism to date, providing a better understanding of the ‘genomic architecture’ underlying the disorder.

The study, published today in cell, used whole genome sequencing (WGS) to examine the entire genomes of over 7,000 individuals with autism, as well as an additional 13,000 siblings and family members.

The team found 134 genes associated with ASD and discovered a number of genetic changes, particularly gene copy number variations (CNVs), likely to be linked to autism, including rare variants linked to ASD in about 14 percent of participants with autism.

Most of the data is drawn from the Autism Speaks MSSNG database, the world’s largest dataset of the whole autism genome, which provides autism researchers with free, open access to thousands of sequenced genomes.

“By sequencing the entire genome of all participants, and with the deep involvement of MSSNG participating families in shaping our research priorities, we maximize the potential for discovery and allow analysis that spans all types of variants, from the smallest DNA changes to those affecting entire chromosomes,” says dr. Stephen Scherer, Senior Scientist, Genetics and Genome Biology and Head of Research at SickKids and Director of the McLaughlin Center at the University of Toronto.

dr. Brett Trost, lead author of the paper and research associate in the Genetics and Genome Biology Program at SickKids, notes that using WGS has allowed researchers to detect variant types that would otherwise be undetectable.

These variants include complex DNA rearrangements as well as expansions of tandem repeats, a finding supported by recent research from SickKids on the link between autism and segments of DNA that are repeated multiple times.

The role of mitochondrial DNA inherited from the mother was also examined in the study and found to account for two percent of autism.

The paper also points to important nuances in the genetics of autism in families with only one person with autism compared to families with multiple individuals with autism, known as multiplex families.

What was surprising to the team was that the “polygenic score”—an estimate of an individual’s likelihood of having autism, calculated by aggregating the effects of thousands of common variants in the genome—was not higher among multiplex families.

“This suggests that autism in multiplex families is more likely to be associated with rare, highly influential variants inherited from parents. “Because the genetics and clinical traits associated with autism are so complex and diverse, large data sets like the ones we used are critical to providing researchers with a clearer understanding of the genetic architecture of autism,” says Trost.

The world’s largest whole-genome sequencing study of autism reveals 134 genes associated with autism
The research team says the study’s data may help expand inquiries into the range of variants that may be associated with ASD, as well as efforts to better understand the contributors to the 85 percent of autistic individuals for whom the genetic cause remains unresolved. Image is in the public domain

The research team says the study’s data may help expand inquiries into the range of variants that may be associated with ASD, as well as efforts to better understand the contributors to the 85 percent of autistic individuals for whom the genetic cause remains unresolved.

U a related study of 325 families with ASD from Newfoundland published this same month in Nature CommunicationsThe team of dr. Scherera found that combinations of spontaneous, rarely inherited, and polygenic genetic factors that come together in the same person can potentially lead to different subtypes of autism.

dr. Suzanne Lewis, a geneticist and researcher at the BC Children’s Hospital Research Institute, who diagnosed many of the families involved in the study, said: “Together, these latest findings represent a huge step forward in better understanding the complex genetic and biological circuits associated with ASD.

“This rich data set also offers an opportunity to dive deeper into examining other factors that may determine an individual’s chance of developing this complex condition to help individualize future treatment approaches.”

funding: Funding for this study was provided by the University of Toronto McLaughlin Centre, Genome Canada/Ontario Genomics, Genome BC, Government of Ontario, Canadian Institutes of Health Research, Canadian Foundation for Innovation, Autism Speaks, Autism Speaks Canada, Brain Child, Children’s Brain Health Network, Qatar National Research Fund, Ontario Brain Institute, SFARI and SickKids Foundation.

See also

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About this genetics and autism research

Author: Jelena Đurkić
Source: Hospital for sick children
Contact: Jelena Đurkić – Hospital for sick children
picture: Image is in the public domain

Original Research: Closed access.
Genomic architecture of autism from comprehensive whole-genome sequence annotation” Stephen Scherer, et al. Cell


Abstract

Genomic architecture of autism from comprehensive whole-genome sequence annotation

Highlights

  • The new edition of MSSNG contains WGS of 11,312 individuals from families with ASD
  • Extensive variant data is available, including SNVs/indels, SVs, tandem repeats and PRS
  • Annotation reveals 134 genes associated with ASD, plus SVs undetectable without WGS
  • A rare, dominant variation has a prominent role in multiplex ASD

Summary

A full understanding of the genetics of autism spectrum disorder (ASD) requires whole genome sequencing (WGS). Introducing the latest edition of the Autism Speaks MSSNG resource, which includes WGS data from 5,100 individuals with ASD and 6,212 non-ASD parents and siblings (total n = 11,312).

Examining a wide array of genetic variants in MSSNG and the Simons Simplex Collection (SSC; n = 9,205), we identified rare variants associated with ASD in 718/5100 individuals with ASD from MSSNG (14.1%) and 350/2419 from SSC (14.1%). 5%). %).

Considering genomic architecture, 52% were variants at the nuclear sequence level, 46% were nuclear structural variants (including copy number variants, inversions, large insertions, uniparental isodisomies and tandem repeat expansions), and 2% were mitochondrial variants.

Our study provides a guide to exploring genotype-phenotype correlations in families carrying rare variants associated with ASD and serves as an entry point to the expanded studies needed to dissect the etiology in the ∼85% of the ASD population that is idiopathic.



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