DNA repeat probe reveals genetic link to

TORONTO – Researchers from the Hospital for Sick Children (SickKids) and the Center for Addiction and Mental Health (CAMH) have found that repeated DNA sequences in the genome may contribute to the risk of developing schizophrenia.

Tandem repeats are a class of DNA sequences where two or more nucleotides, known as DNA building blocks, are repeated adjacent to each other. Sometimes these repetitions can stretch as they are passed down from one generation to the next. As a repeat sequence grows, the likelihood that it can disrupt gene function increases.

Tandem repeat expansions are known to contribute to more than 50 conditions, including Huntington’s disease. Less is known about the role of these tandem repeats in a complex disorder like schizophrenia, which is influenced by the effects of many variants in different genes.

Led by Dr. Ryan Yuen, Genetics and Genome Biology Program Scientist at SickKids, and Dr. Anne Bassett, Senior Scientist at CAMH and the University Health Network, a study published May 12, 2022 in Molecular psychiatry found that people with schizophrenia have a high number of rare tandem repeat expansions that are not typically found in the general population. These tandem repeats are located near genes, and often with other genetic variants, that are known to be associated with schizophrenia.

As part of the study, the team found that the expansions were also present in the sequenced genomes of individuals with a family history of schizophrenia.

“This is the first time that these rare repeat expansions have been assessed at the genome level in schizophrenia. Our results suggest that tandem repeat expansions are an important class of variants that contribute to the risk of schizophrenia,” says Yuen.

Tandem Repeated Expansions Contribute to Errors in How Neurons in the Brain Communicate

Tandem repeats are typically found in noncoding DNA, which means their function is unclear and they can be difficult for researchers to study. The researchers applied a novel computational approach developed by Yuen and his team at SickKids to search and find rare tandem repeat extensions across the entire genome of 257 adults with schizophrenia carefully assessed by Bassett’s team. They compared the data to the genomes of 225 people without psychiatric disorders as well as a cohort of more than 2,500 people from the 1000 Genomes Project, an international genome database.

The study found that tandem repeat expansions contribute to synapse dysfunction – where neurons connect and communicate with each other in the brain – likely by disrupting the process of regulating their associated genes.

The research follows other recently published studies that describe other contributors to schizophrenia risk – one which identified common variant regions and the second which focused on rare protein-disrupting variants.

“We found that genes with tandem repeat expansions overlap with other findings we see in the field. Our study helps fill some of the gaps in our knowledge and highlights the important function of synaptic functions in schizophrenia as well as the complex way in which schizophrenia is affected by different types of genetic variants,” says Yuen, whose team has previously used the same approach to linking tandem repeat expansions to autism spectrum disorders.

Findings help broaden understanding of genetic underpinnings of schizophrenia

Bassett says the findings provide more evidence for the range of genetic risks underlying schizophrenia and related psychiatric disorders.

“Given the biological complexity of schizophrenia, we hope that our findings, in combination with other recent studies in the field, can be used to advance the understanding of this disorder as a disease of the brain to help to de-stigmatize the disease,” says Bassett. “These findings are a big step forward for the future of schizophrenia research.”

Yuen notes that future studies with a larger cohort size are needed to further characterize the role of rare tandem repeats in the condition.

“As we unlock a better understanding of the genetic underpinnings of schizophrenia, we may one day be heading towards a future in which genetic risk factors can be used to individualize treatment approaches for patients.”

The work was supported by SickKids Catalyst Scholar in Genetics, Brain Canada, The Azrieli Foundation, the University of Toronto McLaughlin Centre, Nancy ET Fahrner Award, Dr. Bassett’s Dalglish Chair in 22q11.2 Deletion Syndrome at the University Health Network and University of Toronto and former Tier 1 Canada Research Chair in the Genetics of Schizophrenia and Genomic Disorders, grants from the Canadian Institutes of Health Research (CIHR) and the SickKids Foundation.


About the Hospital for Sick Children (SickKids)

The Hospital for Sick Children (SickKids) is recognized as one of the world’s leading pediatric health care facilities and is Canada’s leading center dedicated to advancing children’s health through the integration of patient care, research and education. Founded in 1875 and affiliated with the University of Toronto, SickKids is one of Canada’s most research-intensive hospitals and has generated discoveries that have helped children around the world. Its mission is to provide the best in complex and specialized family-centered care; pioneering scientific and clinical advances; share expertise; fostering an academic environment conducive to health professionals; and advocate for an accessible, comprehensive and sustainable child health system. SickKids is a founding member of Kids Health Alliance, a network of partners working to create a high quality, consistent and coordinated approach to pediatric health care centered on children, youth and their families. SickKids is proud of its vision of “Healthier Kids. A better world.”

About the Center for Addiction and Mental Health (CAMH)

The Center for Addiction and Mental Health (CAMH) is Canada’s largest mental health and addictions teaching hospital and a leading research center in this field. CAMH combines clinical care, research, education, policy development and health promotion to help transform the lives of people affected by mental illness and addiction. CAMH is fully affiliated with the University of Toronto and is a Pan American Health Organization and World Health Organization Collaborating Center. For more information, visit camh.ca or follow @CAMHnews on Twitter.

Media Contacts
The Hospital for Sick Children (SickKids)
Jessamine’s Luck
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CAMH Media Relations
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