About one in four people with a rare genetic change called a 22q11.2 deletion will develop schizophrenia. A study co-led by UHN has uncovered new clues as to why some people with this high genetic risk go on to develop the condition while others do not.

Schizophrenia is a brain disorder that affects how people think and behave and requires lifelong treatment. While several genetic factors are linked to the illness, a missing portion of DNA in a region called 22q11.2 is one of the strongest known risk factors.

Despite this elevated risk, most people with the deletion do not develop schizophrenia. Therefore, these individuals represent a population that can help researchers understand what additional genetic factors may influence whether the condition develops.

Although schizophrenia is influenced by many different genes, none of the genetic changes identified alone can reliably predict who will get schizophrenia. There is evidence that tandem repeats—repeated stretches of DNA—can raise schizophrenia risk when they become unusually long. These repeats, called tandem repeat expansions (TREs), are like when a word in a sentence is accidentally copied many times. This extra repetition can make gene instructions harder for cells to read properly.

The team, co-led by Dr. Anne Bassett, UHN Senior Scientist, set out to test whether TREs could be a significant genetic modifier for schizophrenia in the presence of a high-risk 22q11.2 deletion. This analysis could also help in determining potential molecular mechanisms of disease and new treatment targets.

By analyzing the genomes of 438 unrelated people with this deletion, the team found that TREs were more common in those diagnosed with schizophrenia. These repeats were often located in DNA regions that help control how genes are expressed. Analysis further revealed that the affected genes are active in brain cells in the prefrontal cortex, an area linked to thinking and behaviour. Some of these genes, including DLGAP2 and DMPK, play key roles in brain development and communication between nerve cells.

These findings suggest that TREs may act as additional genetic risk factors, helping explain why schizophrenia develops in some high-risk individuals. They also provide more insight into how schizophrenia develops at the biological level and support the idea that genome sequencing could be used more widely to help detect complex diseases earlier.

Muyang Cheng is a Doctoral Candidate at The Hospital for Sick Children and the first author of the study.

Dr. Ryan Yuen is a Senior Scientist in Genetics & Genome Biology at The Hospital for Sick Children and an Associate Professor in the Department of Molecular Genetics at the University of Toronto. He is the co-corresponding author of the study.

Dr. Anne Bassett is a Senior Scientist at UHN and a Professor in the Department of Psychiatry at the University of Toronto. She is also the Director of the Clinical Genetics Research Program at the Centre for Addiction and Mental Health (CAMH). She is the co-corresponding author of the study.

This work was supported by the Canadian Institutes of Health Research, the National Institute of Mental Health, Brain Canada, the McLaughlin Centre at the University of Toronto Accelerator grants program, the Canada Research Chairs program, and the inaugural Dalglish Chair in 22q11.2 Deletion Syndrome at the University Health Network and University of Toronto to Dr. Bassett, administered through the UHN Foundation.

Cheng M, Yin Y, Engchuan W, Heung T; International 22q11.2 Brain Behavior Consortium (IBBC); Morrow BE, Bassett AS, Yuen RKC. Genome-wide tandem repeat expansions modify schizophrenia risk in the presence of a 22q11.2 deletion. Mol Psychiatry. 2026 Apr 15. doi: 10.1038/s41380-026-03574-8. Epub ahead of print.