Researchers from The Hospital for Sick Children (SickKids) have uncovered new genes and genetic changes associated with autism in the largest autism whole genome sequencing analysis to date, providing better understanding into the ‘genomic architecture’ that underlies this 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 linked with autism and discovered a range of genetic changes, most notably gene copy number variations (CNVs), likely to be associated with autism, including autism-associated rare variants in about 14 per cent of participants with autism.

“By sequencing the entire genome of all participants, and with deep involvement from the participating families in MSSNG on forming our research priorities, we maximize the potential for discovery and allow analysis that encompasses all types of variants, from the smallest DNA changes to those that affect entire chromosomes,” says Dr. Stephen Scherer, Senior Scientist, Genetics & Genome Biology and Chief of Research at SickKids and Director of the McLaughlin Centre at the University of Toronto.

Dr. Brett Trost, lead author of the paper and a Research Associate in the Genetics & Genome Biology program at SickKids, notes the use of WGS allowed researchers to uncover variant types that would not have otherwise been detectable. These variant types include complex rearrangements of DNA, as well as tandem repeat expansions, a finding supported by recent SickKids research on the link between autism and DNA segments that are repeated many times. The role of the maternally inherited mitochondrial DNA was also examined in the study and found to account for two per cent of autism.

The paper also points to important nuances in autism genetics in families with only one individual with autism compared with families that have multiple individuals with autism, known as multiplex families. Surprising to the team was that the “polygenic score” – an estimation of the likelihood of an individual having autism, calculated by aggregating the effects of thousands of common variants throughout the genome – was not higher among multiplex families.

“This suggests that autism in multiplex families may be more likely to be linked to rare, highly impactful variants inherited from a parent. Because both the genetics and clinical traits associated with autism are so complex and varied, 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 research team says the study data can help expand inquiries into the range of variants that might be linked to autism, as well as efforts to better understand contributors to the 85 per cent of autistic individuals for which the genetic cause remains unresolved. In a linked study of 325 families with autism from Newfoundland published this same month in Nature Communications, Dr. Scherer’s team found that combinations of spontaneous, rare-inherited, and polygenic genetic factors coming together in the same individual can potentially lead to different sub-types of autism.

Dr. Suzanne Lewis, a geneticist and investigator at the BC Children’s Hospital Research Institute who diagnosed many of the families enrolled in the study said, “Collectively, these latest findings represent a massive step forward in better understanding the complex genetic and biological circuitry linked with autism . 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.”

Research in human and animal models points to potential biological and genetic mechanisms contributing to the diversity of behaviours seen in autism. The findings were presented at Neuroscience 2022, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health.

Autism constitutes a diverse group of conditions related to brain development. According to the Centers for Disease Control and Prevention, approximately 1 in 44 children in the U.S. is diagnosed with an autism spectrum disorder, with the diagnosis being four times more common in boys than girls. New research is offering a better understanding of how natural genetic variation impacts brain development and gives rise to the spectrum of behaviours associated with autism, and may contribute to more individualized approaches for supporting people with autism.

Today’s new findings show that:

• A group of genes that have altered activity in autism are also regulated differently in developing male and female brains, potentially contributing to sex differences in autism symptoms and diagnosis. (Donna Werling, University of Wisconsin-Madison)
• Analyses focused on behavioural and genomic differences between sibling pairs reveal genetic locations that could prove relevant to autism-related social difficulties. (Nathaniel Stockham, Stanford University)
• In humans with autism and mouse models of autism, brain imaging reveals two dominant subtypes characterized by altered communication between brain regions. (Marco Pagani, Istituto Italiano Di Tecnologia)

“Studies like those presented today confirm that autism is driven by sources of genetic variation that naturally exist in the human population,” says Nicola Grissom, an assistant professor of psychology at the University of Minnesota who studies individual and sex differences in motivated behaviour and executive function in mouse models. “A better understanding of the genetic components of autism, and appreciation of the neurodiversity occurring naturally among people, may help combat the stigma that still exists around autism.”

A hallmark of autism is the reluctance to make eye contact with others in natural conditions. Although eye contact is a critically important part of everyday interactions, scientists have been limited in studying the neurological basis of live social interaction with eye contact in autism because of the inability to imagine two people’s brains simultaneously.

However, using an innovative technology that enables imaging of two individuals during live and natural conditions, Yale researchers have identified specific brain areas in the dorsal parietal region of the brain associated with the social symptomatology of autism. The study, published Nov. 9 in the journal PLOS ONE, finds that these neural responses to live face and eye contact may provide a biomarker for the diagnosis of autism as well as provide a test of the efficacy of treatments for autism.

“Our brains are hungry for information about other people, and we need to understand how these social mechanisms operate in the context of a real and interactive world in both typically developed individuals as well as individuals with autism,” said co-corresponding author Joy Hirsch, Elizabeth Mears and House Jameson Professor of Psychiatry, Comparative Medicine, and of Neuroscience at Yale.

The Yale team, led by Hirsch and James McPartland, Harris Professor at the Yale Child Study Center, analyzed brain activity during brief social interactions between pairs of adults — each including a typical participant and one with autism — using functional near-infrared spectroscopy, a non-invasive optical neuroimaging method. Both participants were fitted with caps with many sensors that emitted light into the brain and also recorded changes in light signals with information about brain activity during face gaze and eye-to-eye contact.

The investigators found that during eye contact, participants with autism had significantly reduced activity in a brain region called the dorsal parietal cortex compared to those without autism.  Further, the more severe the overall social symptoms of autism as measured by ADOS (Autism Diagnostic Observation Schedule, 2^nd Edition) scores, the less activity was observed in this brain region. Neural activity in these regions was synchronous between typical participants during real eye-to-eye contact but not during gaze at a video face. This typical increase in neural coupling was not observed in autism and is consistent with the difficulties in social interactions.

“We now not only have a better understanding of the neurobiology of autism and social differences but also of the underlying neural mechanisms that drive typical social connections,” Hirsch said.