Study Finds Connections Between Autism Risk Genes

Researchers in Toronto have identified previously unknown connections between genetic risk factors associated with Autism Spectrum Disorder (ASD), including a link to mitochondrial dysfunction. The findings advance the understanding of biological factors underlying symptoms and could lead to more tailored treatments.

ASD is a neurodevelopmental disorder affecting one in 50 Canadians between the ages of 1-17. Symptoms include deficits in communication, cognition, and motor function; seizures; and hyperactivity. Hundreds of risk genes have been linked to the disease, most of which produce proteins involved in important cellular functions. 

However, it is still not known how different genetic risk factors lead to ASD and whether they act independently or through similar molecular pathways to cause the condition. “We also don’t know when, or even where, in the brain these genes are expressed and cause the cellular defects that leads to ASD. Do defects occur during fetal development, after a child is born, or at some later point in their lifespan?” says Dr. Karun Singh, a Senior Scientist at the Donald K. Johnson Eye Institute (DKJEI), part of the Krembil Research Institute at University Health Network. “Our goal for this study was to clarify the roles of specific risk genes in ASD, and whether different genes converge onto common pathways that regulate cell functions, such as energy production and metabolism.”

The study used a protein mapping tool to study 41 risk genes associated with ASD, many of which were not previously known to interact with each other. One of the team’s major findings was that several of the risk genes modulate the activity of mitochondria, the energy factories within cells. Since brain cells are metabolically very active, disruptions to their mitochondrial function can impact brain function.

“The link between ASD risk genes and mitochondrial dysfunction sheds light on how mutations in these genes might change brain cell activity and ultimately cause disease symptoms,” says Dr. Nadeem Murtaza, a postdoctoral researcher in Dr. Singh’s lab.

The study also revealed that the protein-based mapping tool could be used to help classify individuals with ASD who have a shared biological signature. Since ASD is a highly variable disorder, grouping individuals based on the biological factors underlying their symptoms could help researchers develop more tailored treatments in future.

“There is a lot of opportunity for change to occur between the level of the gene sequences, which we are getting a pretty good handle on, and what actually manifests in the patient,” adds Murtaza. “People who have different forms of a genetic disorder might be more connected than we think at the biological level.”

The next step is to apply the protein-mapping technology to patient-specific brain tissue generated in Singh’s lab, where stem cells from a patient’s blood are developed into three-dimensional brain tissues that exhibit that patient’s unique gene and protein profiles. “It would enable us to study a patient’s particular disease mechanisms and eventually, test the effectiveness of different therapies,” says Singh. “This innovative approach will open the door to these technologies being used more widely and being applied to other diseases as well.”

The findings were reported recently in Cell Reports.