Cell has released the largest whole genome sequencing study on autism, revealing 134 autism-related genes

Researchers at SickKids have identified new genes and genetic changes associated with autism spectrum disorder (ASD) in the largest whole-genome sequencing analysis of autism to date, leading to a better understanding of the "genomic structure"
behind the disorder.

The study, published today in the journal Cell, used whole genome sequencing (WGS) to examine the entire genomes
of more than 7,000 people with autism, as well as another 13,000 siblings and family members.
The team identified 134 genes associated with ASD and found a range of genetic changes, most notably gene copy number variants (CNVs) that may be associated with autism, including rare variants
associated with ASD in about 14 percent of autistic participants.

Much of the data comes from the Autism Voice MSSNG database, the world's largest autism genome-wide dataset, providing autism researchers with free, open access
to thousands of sequenced genomes.

"By sequencing the entire genome of all participants and forming our research focus with the deep involvement of MSSNG-participating families, we maximize the potential of our findings and allow analysis to include all types of variation, from the smallest DNA changes to those affecting the entire chromosome," said Dr.
Stephen Scherer, senior scientist and research director at SickKids and director of the McLaughlin Centre at the University of Toronto
。

Dr.
Brett Trost, lead author of the paper and an assistant researcher in SickKids' Genetics and Genomic Biology Project, noted that using WGS allowed researchers to discover types
of variants that would otherwise be undetectable.
These variant types include complex DNA rearrangements, as well as tandem repeat amplification, a finding supported by SickKids' recent research on the link between autism and repeating DNA fragments many times
.
The study also examined the role of mitochondrial DNA inherited by the mother and found that it accounted for 2%
of autism.

The paper also points to important nuances in autism genetics between families with only one autistic person and families with multiple autistic people (i.
e
.
, multiple birth families).
To the team's surprise, the "polygenic score" — an estimate of an individual's likelihood of developing autism, calculated by aggregating the effects of thousands of common variants in the genome — was not high
in polygenic families.

"This suggests that autism in multiple families may be more likely to be associated with
rare, highly impactful variants inherited from parents.
" Because the genes and clinical traits associated with autism are so complex and variable, large datasets like the one we use are critical to giving researchers a clearer understanding of the genetic architecture of autism," Trost said
.

The research team says the research data could help expand the investigation of the range of variants that may be linked to autism spectrum disorder, as well as better understand factors
whose genetic causes remain unaddressed in 85 percent of individuals with autism.
In a related study of 325 families with autism spectrum disorder from Newfoundland, published in Nature Communications the same month, Dr.
Scheler's team found that a combination of spontaneous, rare genetic and polygenic genetic factors in the same body may contribute to different subtypes of autism
.

Dr.
Suzanne Lewis, a geneticist and investigator at the BC Children's Hospital Research Institute, has made diagnoses
for many of the families involved in the study.
"Taken together, these latest findings represent a major step
forward in better understanding the complex genetic and biological circuits associated with autism spectrum disorders," she said.
This rich dataset also provides an opportunity to delve deeper into other factors that may determine an individual's odds of developing this complex disease to help develop personalized future treatments
.
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