Most research about the genetics of schizophrenia has sought to
understand the role that genes play in the development and heritability of
schizophrenia. Many discoveries have been made, but there have been many
missing pieces. Now, UNC School of Medicine scientists 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.
Published in Nature Communications, the study
co-led by senior author Jin Szatkiewicz, PhD, associate professor in the UNC
Department of Genetics, suggests that rare structural genetic variants could
play a role in 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.”
Previous studies
on the genetics of schizophrenia have primarily 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, leaving a large portion of the genome a mystery,
as it potentially relates to schizophrenia.
In the Nature Communications study, Szatkiewicz and
colleagues examined 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, new
discoveries were made. Previously undetectable mutations in DNA were found that
scientists had never seen before in schizophrenia.
In particular,
this study highlighted the role that a three-dimensional genome structure known
as topologically associated domains (TADs) 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, gene expression may be changed in undesirable ways that
could result in congenital defects, formation of cancers, and developmental
disorders. This study found 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 also contribute to the development of schizophrenia. This study
was the first to discover the connection between anomalies in TADs and the
development of schizophrenia.
This work has
highlighted TADs-affecting structural variants as prime candidates for future
mechanistic studies of the biology of 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.”
This study will
be combined with other WGS studies in order to increase the sample size to
further confirm these results. This research will also help the scientific
community build on the unfolding genetic mysteries of schizophrenia.
Journal article: https://www.nature.com/articles/s41467-020-15707-w
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