Genome sequencing links rare tandem repeats to genes associated with schizophrenia
In one of the largest genome sequencing investigations, scientists have identified that rare repetitions in certain DNA sequences are significantly more common among people with schizophrenia.
The recent study published in Molecular Psychiatry observed that in individuals with schizophrenia, rare tandem repeats are more present in genes that primarily impact synaptic and neuronal signaling functions, affecting how neurons in the brain communicate with each other.
Tandem repeat expansions describe the repetition of short lengths of DNA multiple times in a row and are known to contribute to over 60 conditions, often with a heredity component.
Led by Dr. Ryan Yuen, Senior Scientist in the Genetics & Genome Biology program at The Hospital for Sick Children (SickKids) and Dr. Jin Szatkiewicz at the University of North Carolina School of Medicine, the international team also found that rare tandem repeat expansions may explain the cause in seven per cent of individuals with schizophrenia.
The occurrence and location of these tandem repeats was analyzed with computational methods developed at The Centre for Applied Genomics (TCAG) at SickKids. The team examined the entire genomes of 474 individuals in Canada with and without a diagnosis of schizophrenia and compared it to 2,088 schizophrenia cases and controls in Sweden, with similar results.
“Until recently, we have lacked the technology to dive into tandem repeats at such a large scale,” says Yuen. “Advancements in genetic sequencing and the capabilities we have at SickKids allow us to not only explore the number of tandem repeats, but their impact on specific genes implicated in schizophrenia.”
The insights generated from this study add to a growing understanding of the genetic contributors of schizophrenia, including recent research led by Yuen and Dr. Anne Bassett, a Senior Scientist at the Centre for Addiction and Mental Health (CAMH) and University Health Network, that identified a higher number of tandem repeat expansions in individuals with schizophrenia.
Research into the role of tandem repeats in other genetic diseases is already underway. In a study published earlier this week in Nature, Yuen was part of a research team that identified tandem repeat expansions in 2,622 cancer genomes across 29 cancer types, suggesting new opportunities for therapies that target tandem repeats. Previous SickKids research has also highlighted the role of rare tandem repeats in autism as well as Huntington's disease.
“Beyond identifying tandem repeats and the affected genes, our research offers a new way to think about treatment for complex, genetic disorders,” says Yuen.
This research was supported by SickKids Foundation, SickKids Catalyst Scholar in Genetics, Brain Canada, The Azrieli Foundation, University of Toronto McLaughlin Centre, Nancy E.T. Fahrner Award, grants from the Canadian Institutes of Health Research (CIHR), National Institute of Mental Health and SciLifeLab National Project.