The link between tandem repeats and development of Schizophrenia

Each human cell is distinct because it is written in the DNA language. When a pattern of one or more nucleotides, the fundamental building block of DNA made up of the chemicals cytosine (C), adenine (A), guanine (G), and thymine (T), is repeated multiple times in tandem, it is known as a tandem repeat. CAG CAG CAG, in which the letter CAG is repeated three times, is one illustration.

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The UNC School of Medicine lab of Jin Szatkiewicz, PhD, associate professor of genetics, and colleagues performed one of the first and largest investigations of tandem repeats in schizophrenia, elucidating their role in the development of this debilitating disease. They did this using cutting-edge whole-genome sequencing and machine learning techniques.

The study, which was published in the journal Molecular Psychiatry, demonstrates that people with schizophrenia had 7% more rare tandem repeats in their genomes than people without the disease.

They also noticed that the tandem repeats were not distributed randomly across the genome, but were primarily found in genes known to be important in schizophrenia and critical for brain function.

We think this discovery opens doors for future functional studies on the precise biological mechanism of such variants. Understanding the biological cause of schizophrenia will enable future development of diagnostic tests, effective pharmaceuticals, and personalized treatments.”

Jin Szatkiewicz, PhD, Associate Professor, Department of Genetics, School of Medicine, UNC Health

Szatkiewicz is also an adjunct assistant professor of psychiatry.

Typically, tandem repeats have no detrimental effects on health. Tandem repeats, depending on where they are in the genome and how long they are, could cause disease, though. For instance, a tandem repeat that has been abnormally expanded in the HTT gene is the cause of Huntington’s disease.

Once the cytosine-adenine-guanine (CAG) sequence on the HTT gene repeats more than 36 times, the disease will start to manifest. Longer repeat expansions result in abnormal protein byproducts with extended glutamine tracks, which are toxic to brain cells.

These repeats are inherited and tend to get longer and longer in subsequent generations as the disease gets worse or the onset age gets younger.

Szatkiewicz and her team’s most recent study examined the entire genomes of 2,100 people to identify tandem repeats that appeared abnormally long and were either rare or unique.

The team was able to compare these lengthy, uncommon repeat DNA sequence samples from individuals with schizophrenia to samples from study participants who did not because all participants were granted access to their medical records. This gave the researchers the opportunity to identify which of these tandem repeats might contribute to the emergence of schizophrenia.

The authors of this study used gene network analysis to show that synaptic and neuronal signaling functions are primarily affected by genes with rare tandem repeats found in schizophrenia.

Additionally, these genes have undergone a great deal of evolutionary conservation, which suggests that they serve important biological functions and, consequently, that tandem repeats could have a significant effect.

The UNC School of Medicine researchers next worked with researchers from The Hospital for Sick Children in Toronto to see if this elevated level of rare tandem variants would also be discovered in a different set of samples that had been collected independently.

The Canadian study confirmed the Szatkiewicz findings, demonstrating the strength of the recently discovered association between tandem repeats and schizophrenia.

We think this is an important study. We are confident our work sheds significant light on the role of tandem repeat DNA mutations play in the development of schizophrenia.”

Ryan Yuen, PhD, Senior Scientist, Senior Scientist, Hospital for Sick Children

Yuen is also an assistant professor of molecular genetics at the University of Toronto.