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

Abstract: 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 probable association with ASD, including autism-related variants in 14% of individuals 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.

A study published today in cell phone, used whole-genome sequencing (WGS) to examine the entire genomes of more than 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, most notably gene copy number variations (CNVs), that are 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 autism genome-wide dataset, which provides autism researchers with free, open access to thousands of sequenced genomes.

“By whole-genome sequencing of all participants and the deep involvement of MSSNG families in shaping our research priorities, we maximize the potential for discovery and enable analysis that spans all types of variants, from the smallest DNA changes to those affecting entire chromosomes,” he says. Dr. Stephen Scherer, Senior Scientist, Genetics and Genomic Biology and Research Lead 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 & Genome Biology program at SickKids, notes that the use of WGS has allowed researchers to discover types of variants that would otherwise be undetectable.

These variant types include complex DNA rearrangements as well as tandem repeat expansions, 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 be responsible 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 the likelihood that an individual has autism, calculated by adding up the effects of thousands of common variants across the genome—was not higher among the multiplex families.

“This suggests that autism in multiplex families is more likely to be associated with rare, highly influential variants inherited from parents. “Because both 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 research into the range of variants that may be associated with ASD, as well as efforts to better understand the factors that contribute to the 85 percent of autistic individuals for whom the genetic cause remains unresolved. The image is in the public domain

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

IN a related study of 325 families with ASD from Newfoundland published this same month in Nature CommunicationsDr. Scherer’s team found that combinations of spontaneous, rarely inherited, and polygenic genetic factors that accumulate 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 major step forward in better understanding the complex genetic and biological circuitry 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 in order to individualize future treatment approaches.”

Financing: 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, Kids Brain Health Network, Qatar National Research Fund, Ontario Brain Institute, SFARI and SickKids Foundation.

See also

This shows someone pulling a puzzle piece out of the model's head

About this news about genetics and autism research

Author: Jelena Djurkic
Source: Hospital for sick children
Contact: Jelena Đurkić – Hospital for sick children
Picture: The image is in the public domain

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


Abstract

Genomic architecture of autism from comprehensive whole-genome sequence annotation

Accents

  • The new edition of MSSNG contains WGS of 11,312 individuals from families with ASD
  • Extensive variant data 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

Abstract

A full understanding of the genetics of autism spectrum disorder (ASD) requires whole genome sequencing (WGS). We present the latest edition of the Autism Speaks MSSNG resource, which includes WGS data from 5100 individuals with autism and 6212 parents and siblings without autism (total n = 11312).

Examining a large selection of genetic variants in the MSSNG and the Simons Simplex Collection (SSC; n = 9205), we identified rare variants associated with ASD in 718/5100 individuals with ASD from the MSSNG (14.1%) and 350/ 2419 from SSC (14.5). %).

Regarding 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 ASD-associated variants and serves as an entry point for expanded studies needed to dissect etiology in the ~85% of ASD populations that remain idiopathic.

title_words_as_hashtags]

Leave a Comment

Your email address will not be published. Required fields are marked *