Whole Genome Sequencing Reveals Genetic Risks of Schizophrenia

In the largest-ever whole genome sequencing study of schizophrenia, researchers discovered that rare structural genetic variants could play a role in the development of the disorder.

The findings could help develop precision medicine therapies that may improve schizophrenia patient outcomes.

Previous studies on the genetics of schizophrenia have primarily used common genetic variations known as SNPs, rare variations in the part of DNA that provide instruction for making proteins, or very large structural variations. These studies give snapshots of the genome, leaving a large portion of the genome a mystery as it potentially relates to schizophrenia.

Scientists at University of Chapel Hill (UNC) School of Medicine set out to provide a more complete picture of the role the human genome plays in this disease. Using a method called whole-genome sequencing, researchers analyzed the genes of 1,165 people with schizophrenia and 1,000 controls, the largest known whole genome sequencing study of schizophrenia ever.

The findings highlighted the role that a three-dimensional genome structure known as topologically associated domains (TADs) could play in schizophrenia development. TADs are distinct regions of the genome with strict boundaries between them that keep the domains from interacting with genetic material in neighboring TADs. Shifting or breaking these boundaries enables interactions between genes and regulatory elements that normally would not interact.

When these interactions occur, gene expression may be changed in undesirable ways that could result in congenial defects, cancers, and developmental disorders. In this study, researchers discovered that extremely rare structural variants affecting TAD boundaries in the brain occur significantly more in people with schizophrenia than in those without it.

Structural variants are large mutations that may involve missing or duplicated gene sequences, or sequences not in the typical genome. This finding suggests that misplaced or missing TAD boundaries may also contribute to the development of schizophrenia. This study was the first to discover the connections between anomalies in TADs and the development of schizophrenia.

"Our results suggest that ultra-rare structural variants that affect the boundaries of a specific genome structure increase risk for schizophrenia," Szatkiewicz said. "Alterations in these boundaries may lead to dysregulation of gene expression, and we think future mechanistic studies could determine the precise functional effects these variants have on biology."

As the fields of precision medicine and genetics have evolved, healthcare researchers have sought to understand the role genes play in a wide range of cognitive disorders.

In a recent study from Mount Sinai, researchers conducted a large-scale genetic sequencing study of autism spectrum disorder (ASD) and identified 102 genes associated with the condition, which could help clinicians better understand the disorder and how to treat it.

“This is a landmark study, both for its size and for the large international collaborative effort it required. With these identified genes we can begin to understand what brain changes underlie ASD and begin to consider novel treatment approaches,” said Joseph D. Buxbaum, PhD, Director of the Seaver Autism Center for Research and Treatment at Mount Sinai, and Professor of Psychiatry, Neuroscience, and Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai.

The results of the schizophrenia study will be combined with other whole genome sequencing studies to increase the sample size to further confirm these findings. This research could help the scientific community better understand the underlying role of genetics in schizophrenia.

"A possible future investigation would be to work with patient-derived cells with these TADs-affecting mutations and figure out what exactly happened at the molecular level," said Szatkiewicz, an adjunct assistant professor of psychiatry at UNC.

"In the future, we could use this information about the TAD effects to help develop drugs or precision medicine treatments that could repair disrupted TADs or affected gene expressions which may improve patient outcomes."