A team from the University of North Carolina School of Medicine has uncovered new genetic variation linked to schizophrenia. The researchers identified an abundance of rare tandem repeat expansions (TREs) in patients with the condition, and further collaboration with scientists at The Hospital for Sick Children in Toronto strengthened the findings. The work, published in Molecular Psychiatry, describes the impact of this variation on the development of schizophrenia.
Can you repeat yourself?
TREs are found all over the genome and are typically harmless. However, in certain cases, a long TRE can result in the formation of toxic products and cause disease. Until recently, TREs were very difficult to study. The repetitive nature of these sections of DNA made assembly of short-reads troublesome, causing problems in the construction of whole genome sequences. Fortunately, technology has now been developed that can help to elucidate the positions, lengths and system-wide impacts of these repeated regions.
Jin Szatkiewicz and her team chose to investigate TREs in schizophrenia. Schizophrenia is a devastating mental health condition, characterised by symptoms including hallucinations and psychosis. The illness is known to have a hereditary element and is relatively well studied, yet the role of TREs in disease onset has yet to be uncovered.
A rare find
The team analysed over 4,000 genomes to detect TREs and their abundance in the population. Of these, over 1,000 genomes came from schizophrenia patients previously sequenced by the group. Roughly 21,000 TREs were identified – many of which were novel – and 603 were defined as rare. An outline of the study can be seen in Figure 1 below.
Figure 1: Flowchart showing the study design. The flowchart describes the origins of the data, the definition of “rare” in the current study, and information on burden analysis. TR = Tandem Repeat. Adapted from Wen et al (2022).
Rare TREs were observed to be in higher abundance in schizophrenia patients than in the control group. The team theorised that, as seen in Fragile X syndrome, these TREs may lie within genes known to be associated with schizophrenia and other neurological disorders. Armed with a wealth of knowledge about genetic variation linked to these conditions, the group discovered that rare TREs were enriched in regions previously associated with schizophrenia, particularly in brain-expressed genes. Specifically, the variation occurred in genes which impact synaptic and neuronal signalling. Disruption to these pathways has previously been implicated as a fundamental feature of the schizophrenia phenotype.
Working in tandem
Hoping to replicate the results, the researchers teamed up with scientists from The Hospital for Sick Children in Toronto. This new independent cohort consisted of 252 schizophrenia patients and 222 controls, all of European ancestry. The group were able to replicate all the significant findings through association analysis of the new cohort and meta-analyses using both datasets. The replicability of the results indicates a true association between these TREs and schizophrenia. Co-author Ryan Yuan (Senior Scientist at the Hospital for Sick Children) stated that the team are “confident [their] work sheds significant light” on the role of TREs in the onset of the condition.
This study, one of the first of its kind, implies a significant link between rare tandem repeat expansions and schizophrenia. This knowledge could help to improve diagnosis and treatment for patients. Uncovering the mechanisms through which these TREs impact neurological function is vital in understanding how schizophrenia develops, but could also help in elucidating the role TREs play in other neurological conditions such as autism spectrum disorder. The team acknowledge certain limitations in the study, namely sample size, and stress the importance of collaborative efforts to obtain larger cohorts. Szatkiewicz said that the work “opens doors for future functional studies.”