Genomic Structural Variants Discovered in Patients With Schizophrenia

By Hillary Eames
Monday, January 25, 2021

A groundbreaking study reveals an ultra-rare genomic variant often presents in patients with schizophrenia, providing more information on effective treatment options for a complicated disorder.

The role of genetics in the development of schizophrenia has remained comparatively complex to understand. Schizophrenia is predominately a hereditary disease, with patients being more than six times as likely to present with schizophrenia if a close relative has the disorder. Schizophrenia is not caused by a single genetic mutation, but a complex combination of genetic changes with compounding effects. Even as recently as February 2018, the U.S. National Library of Medicine noted that the way genetic changes relate to schizophrenia are “not well understood,” and further knowledge would require robust and continuous research. While several studies have been performed to understand how a patient’s genes can lead to the development and/or heritability of the disorder, gaps within research have remained.

However, great strides have been made recently to close those gaps. A 2020 study performed at the University of North Carolina at Chapel Hill and published in Nature Communications illustrates an integral connection between genomic structural variants and schizophrenia. Before this study, research about schizophrenia’s heritability primarily reviewed common genetic variations in single nucleotide polymorphisms, occurring within a part of DNA that provides instructions on protein synthesis. While these studies highlighted portions of the genome, it was not until Jin Szatkiewicz, PhD, associate professor, Department of Genetics and adjunct assistant professor, Department of Psychiatry at the University of North Carolina at Chapel Hill and her associates used whole-genome sequencing to examine the entire genome. The complete picture of the genome led to remarkable new discoveries: specifically, variants within topologically associating domains (TADs) are more likely to be present in patients with schizophrenia.

“Our results suggest that ultra-rare structural variants that affect the boundaries of [this] specific genome structure increase the risk of schizophrenia,” Szatkiewicz says in a press release. “Alterations in these boundaries may lead to dysregulation of gene expression.”

“Whole-genome sequencing can potentially provide a more complete enumeration of etiological genetic variations and uncover novel variants previously undetectable using exome sequencing or single nucleotide polymorphism arrays.”
— Jin Szatkiewicz, PhD, associate professor, department of genetics and adjunct assistant professor, department of psychiatry at the University of North Carolina at Chapel Hill

Methods and Findings: How TAD Variants Affect the Brain With Schizophrenia

In this study, the UNC School of Medicine researchers found that extremely rare structural variants within TAD boundaries are significantly more common in patients with schizophrenia than in patients without. Structural variants are large mutations with duplicated or missing gene sequencing. In the case of patients with schizophrenia, structural variants were found within misplaced or missing TAD boundaries, suggesting that TAD-affecting structural variants may contribute to the disorder’s development.

Since seminal research published in 2012, scientists have recognized TADs as a type of 3D genomic structure, forming regions within the genome that assist with genomic communications. These points of contact, along with others, help to regulate gene expression in chromosomes. TADs in particular have boundaries to prevent domains from interacting with genetic material in neighboring genomic regions. When these boundaries are compromised, genes that would not commonly interact are able to do so. These interactions can affect gene expression, causing cancers, congenital defects and developmental disorders. However, this study was the first to connect abnormalities within TAD boundaries and the development of schizophrenia.

To conduct this study, Szatkiewicz et al. received international-collaboration-pooled funding from the National Institute of Mental Health and Sweden’s SciLife Labs, as the high cost of whole-genome sequencing has prevented it from being used in more studies. Whole-genome sequencing was performed on 1,000 control subjects without schizophrenia and 1,165 patients with the disease, making this the largest known study of its kind in history.

“We have applied for funding to carry out functional work with patient-derived cells in the near future,” Szatkiewicz tells MD News. “Once funded, we will be able to obtain cells that carry those TAD-affecting mutations, differentiate them into relevant neuronal subtypes, and functionally characterize different neurons using genome technologies that can reveal the precise functional effects of these mutations.”

The Future of Genomics in Mental Health

The study’s findings show promise for the future of understanding the underlying biological mechanisms not only of schizophrenia but of mental illness in general.

“Understanding the role of genomics in mental illness...will enable the development of more effective diagnosis [such as] genetic testing, and treatment [such as] optimizing treatment protocol, selecting effective drugs according to one’s genetic makeup, and using gene editing tools to modify altered genome structures and restore proper function or target affected genes or their products,” Szatkiewicz says. “Genetic testing will likely become more prevalent, and a genetic causal factor for mental illness may help reduce stigma and increase compassion for individuals.”

The ability to find effective treatment for schizophrenia could be especially revolutionary for individuals with the disorder. Untreated schizophrenia can be disabling to individuals with the disorder, reducing their quality of life, but finding the best medication sometimes takes longer than patients or physicians would prefer.

“Finding the right medication for mental illness sometimes involved [a] prolonged trial-and-error period,” Szatkiewicz says. “Genetic testing will be able to help narrow down the options much more quickly.”