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Whole-Genome Study Finds Previously Undetected Schizophrenia Mutations

A new study, published in Nature Communications, suggests that ultra-rare structural genetic variants could play a role in schizophrenia.

Most genetic research on schizophrenia has sought to understand the role genes play in the development and heritability of schizophrenia. And while many discoveries have been made, there are still many missing pieces.

Now, scientists at the University of North Carolina (UNC) School of Medicine have conducted the largest-ever whole genome sequencing study of schizophrenia to provide a more complete picture of the role the human genome plays in this disease.

“Our results suggest that ultra-rare structural variants that affect the boundaries of a specific genome structure increase risk for schizophrenia,” said senior author Jin Szatkiewicz, PhD, associate professor in the UNC Department of Genetics.

“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.”

Previous research on the genetics of schizophrenia has mostly involved using common genetic variations known as SNPs (alterations in common genetic sequences and each affecting a single nucleotide), rare variations in the part of DNA that provide instructions for making proteins, or very large structural variations (alterations affecting a few hundred thousands of nucleotides).

These studies give snapshots of the genome as it potentially relates to schizophrenia, but leave a large portion of the genome a mystery.

In the new study, the research team looked at the entire genome using a method called whole genome sequencing (WGS). The primary reason WGS hasn’t been more widely used is that it is very expensive.

For this study, an international collaboration pooled funding from National Institute of Mental Health grants and matching funds from Sweden’s SciLife Labs to conduct deep whole genome sequencing on 1,165 people with schizophrenia and 1,000 controls — the largest known WGS study of schizophrenia ever.

As a result, previously undetectable mutations in DNA were found that researchers had never seen before in schizophrenia.

In particular, the findings emphasize the role that topologically associated domains (TADs) (a three-dimensional genome structure) could play in the development of schizophrenia. 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 allows interactions between genes and regulatory elements that normally would not interact.

When these interactions occur, there may be negative outcomes in gene expression that could result in congenital defects, formation of cancers, and developmental disorders.

The researchers discovered that extremely rare structural variants affecting TAD boundaries in the brain occur significantly more often in people with schizophrenia than in those without it. Structural variants are large mutations that may involve missing or duplicated genetic sequences, or sequences that are not in the typical genome.

This finding suggests that misplaced or missing TAD boundaries may contribute to the development of schizophrenia, and TADs-affecting structural variants may be prime candidates for future schizophrenia studies.

“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.”

Source: University of North Carolina Health Care

Whole-Genome Study Finds Previously Undetected Schizophrenia Mutations

Traci Pedersen

Traci Pedersen is a professional writer with over a decade of experience. Her work consists of writing for both print and online publishers in a variety of genres including science chapter books, college and career articles, and elementary school curriculum.

APA Reference
Pedersen, T. (2020). Whole-Genome Study Finds Previously Undetected Schizophrenia Mutations. Psych Central. Retrieved on December 4, 2020, from
Scientifically Reviewed
Last updated: 24 Apr 2020 (Originally: 24 Apr 2020)
Last reviewed: By a member of our scientific advisory board on 24 Apr 2020
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