The largest complete genome sequencing study of autism has identified 134 genes related to the development of autism spectrum disorder (ASD), which helps to better understand the “genomic architecture” of the same. The authors of the work are researchers from the Hospital for Sick Children (SickKids), who examined the complete genomes of more than 5,100 individuals with autism along with those of another 6,212 people who were siblings or relatives without ASD.
In addition to the 134 genes, they have also discovered a variety of genetic changes, particularly gene copy number variations (CNVs), that are likely associated with the causes of autism, including rare variants associated with ASDs, in about 14% of participants with autism. Most of the data came from the Autism Speaks MSSNG database, the largest complete autism genome dataset in the world.
“By sequencing the full genome of all participants, and with the deep involvement of MSSNG participating families in shaping our research priorities, we maximize discovery potential and enable analysis spanning all types of variants, from changes from the smallest DNA cells to those that affect entire chromosomes,” explained Dr. Stephen Scherer, Senior Scientist in Genetics and Genome Biology and Head of Research at SickKids, and Director of the McLaughlin Center at the University of Toronto.
“Autism in multiplex families –those in which there are several individuals with ASD– is more likely to be related to rare and high-impact variants inherited from one parent”
The use of whole genome sequencing has allowed researchers to discover types of variants that might not otherwise have been detected, including complex DNA rearrangements and tandem repeat expansions, something that had already been found in recent SickKids research. about the link between autism and repeatedly repeating segments of DNA, said Dr. Brett Trost, lead author of the paper and a research associate in the Genetics and Genome Biology program at SickKids. The study, which has been published in Cell, also looked at the role played by mitochondrial DNA inherited from the mother and found that it accounts for 2% of autism.
Better understand the genetic and biological circuitry related to ASD
The study also reveals important nuances in the genetics of autism in families with a single individual with autism compared to families with multiple individuals with ASD, known as multiplex families. The “polygenic score,” which is calculated by adding the effects of thousands of common variants across the genome, was not higher among the multiplex families, surprising the researchers.
“This suggests that autism in multiplex families is more likely to be related to rare and high-impact variants inherited from one parent. Because both the genetics and clinical traits associated with autism are so complex and varied, large data sets like the ones we use are critical to providing researchers with a clearer understanding of the genetic architecture of autism,” says Trost.
In the opinion of the authors of the study, their findings can contribute to expanding research on the series of variants that could be related to ASD and that serve to better understand autistic people for whom the genetic cause remains unresolved and who constitute the 85% of the cases. In another related study involving 325 Newfoundland ASD families, recently published in Nature Communications, Dr. Scherer’s team found that combinations of spontaneous, poorly inherited, and polygenic genetic factors occurring in the same individual they 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 enrolled in the study, concludes: “Taken together, these latest findings represent a major step forward in better understanding the complex genetic and biological circuit related to ASD. This rich data set also offers the opportunity to further examine other factors that may determine an individual’s chance of developing this complex condition to help individualize future treatment approaches.”
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