Rare genetic phenomenon linked to neuronal function and schizophrenia – Neuroscience News

Summary: People with schizophrenia have significantly higher rates of tandem repeats in their genome, up to 7% more than people without a mental health disorder. The genes were mainly found in genes crucial for brain function.

Source: A C

In our cells, the language of DNA is written, making each of us unique. A tandem repeat occurs in DNA when a pattern of one or more nucleotides – the basic structural unit of DNA encoded in the basis of the chemicals cytosine (C), adenine (A), guanine ( G) and thymine (T) – is repeated several times. times in tandem. An example might be: CAG CAG CAG, in which the CAG pattern is repeated three times.

Now, using cutting-edge whole genome sequencing and machine learning techniques, the UNC School of Medicine lab of Jin Szatkiewicz, Ph.D., associate professor of genetics, and his colleagues have conducted one of the first and largest investigations of tandem repeats in schizophrenia, elucidating their contribution to the development of this devastating disease.

Published in the journal Molecular psychiatry, research shows that people with schizophrenia had a significantly higher rate of rare tandem repeats in their genomes, 7% more than people without schizophrenia. And they observed that the tandem repeats were not randomly located throughout the genome; they have mainly been found in genes crucial for brain function and known to be important in schizophrenia, according to previous studies.

“We believe this finding opens doors for future functional studies of the precise biological mechanism of these variants,” said Szatkiewicz, who is also an adjunct assistant professor of psychiatry.

“Understanding the biological cause of schizophrenia will enable the future development of diagnostic tests, effective pharmaceuticals, and personalized treatments.”

Tandem reps generally do not have negative health implications. However, depending on where the tandem repeats are located in the genome and how long they last, they may contribute to disease. For example, Huntington’s disease is caused by a tandem repeat in the HTT gene that has been abnormally developed. Disease onset will occur once the cytosine-adenine-guanine (CAG) sequence repeats more than 36 times on the HTT gene.

Longer repeat expansions lead to abnormal protein products with an extended glutamine trail that is toxic to brain cells. These repeats are hereditary and tend to become longer and longer in successive generations with increasing disease severity or decreasing age of onset.

In their current study, Szatkiewicz and his team examined the entire genomes of 2,100 individuals to find tandem repeats that appeared abnormally long and were unique or rare. Because all participants gave access to their medical records, the team was able to compare these samples of long and rare repeated DNA sequences from people with schizophrenia against samples from people in the study who did not. had not. This allowed the researchers to determine which of these tandem repeats may be involved in the development of schizophrenia.

Using gene network analysis, the authors of this study demonstrated that genes with rare tandem repeats found in schizophrenia primarily impact synaptic and neuronal signaling functions.

Moreover, these genes are highly conserved during evolution, indicating important biological functions and therefore the significant impact that tandem repeats could exert.

The UNC School of Medicine researchers then collaborated with scientists at the Hospital for Sick Children in Toronto to see if this increased level of rare tandem variants would also be found in another group of independently collected samples. .

Szatkiewicz’s findings were replicated in the Canadian investigation, indicating that this newly discovered link between tandem repeats and schizophrenia is quite strong.

“We think this is an important study,” said co-lead author Ryan Yuen, Ph.D., senior researcher at The Hospital for Sick Children and assistant professor of molecular genetics at the University. of Toronto. “We are confident that our work sheds significant light on the role played by DNA tandem repeat mutations in the development of schizophrenia.”

About this news about schizophrenia and genetics research

Author: Press office
Source: A C
Contact: Press office – UNC
Image: Image is in public domain

Original research: Free access.
“Rare tandem repeats associated with genes involved in synaptic and neuronal signaling functions in schizophrenia” by Jia Wen et al. Molecular psychiatry

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Summary

Rare tandem repeat expansions are associated with genes involved in synaptic and neuronal signaling functions in schizophrenia

Tandem repeat expansions (TREs) are associated with over 60 single gene disorders and have recently been implicated in complex disorders such as cancer and autism spectrum disorders. The role of TREs in schizophrenia is emerging. In this study, we performed a genome-wide investigation of TREs in schizophrenia.

Using genome sequence data from 1154 Swedish schizophrenia cases and 934 ancestry-matched population controls, we detected genome-wide rare TREs (<0.1% population frequency) which have motifs 2 to 20 base pairs long. We find that the proportion of individuals carrying rare REEs is significantly higher in the schizophrenic group.

There is a significantly higher burden of rare TREs in schizophrenia cases than in controls in gene regions, particularly in post-synaptic genes, in genes overlapping brain expression quantitative trait loci, and in gene regions. genes expressed in the brain that are differentially expressed between schizophrenia cases and controls.

We demonstrate that genes associated with TREs are more constrained and primarily impact synaptic and neuronal signaling functions.

These findings were replicated in an independent Canadian sample of 252 schizophrenia cases of European ancestry and 222 ancestry-matched controls. Our results confirm the involvement of rare TREs in the etiology of schizophrenia.