Shedding light on the mechanisms behind schizophrenia

Facilitated by the SciLifeLab National Genomics Infrastructure (NGI) and staff from the SciLifeLab Bioinformatics Platform (NBIS), researcher from Lund University, Chalmers University, Uppsala University, Karolinska Institutet (KI) and the University of North Carolina (UNC), USA, have revealed a new mechanism, involved in the development of schizophrenia.

To understand how genes play a part in schizophrenia a lot of research has been conducted in the area and even though many secrets have been revealed, many pieces of the puzzle are still missing.

Earlier studies have mainly focused on common genetic variations known as single nucleotide polymorphism (SNP), large copy number variants (CNV), or the sequencing of exomes.

In a new study, led by Patrick Sullivan (KI/UNC) and Jin Szatkiewicz (UNC) and published in Nature Communications, researchers used whole genome sequencing (WGS) on a massive 1,165 cases and 1000 controls making this the largest known WGS study of schizophrenia to date. The cases were selected from the Swedish schizophrenia study and sequenced by the SNP&SEQ, part of the NGI unit, in Uppsala. The control WGS data came from the SweGen project.

The sequencing revealed new information in the form of previously undetectable mutations and structural variations – large mutations that may involve missing genes, duplicated genes or genes that are not in the typical sequence – in the DNA.

According to the study, a type of three-dimensional genome structures, known as topologically associated domains (TADs), might play an important role in the development of schizophrenia. Within TADs, DNA sequences interact frequently but strict boundaries between them keep DNA from interacting with DNA from neighboring TADs. If these boundaries are somehow shifted or broken, allowing cross interaction, it could result in congenital defects, tumours, and developmental disorders.

The study found that this occurred significantly more often in the brains of people with schizophrenia than those without the disease, due to extremely rare structural variations, impacting TAD boundaries in affected individuals. This is the first time a link between defect TADs and the development of schizophrenia has been presented.

The new information has highlighted TAD-affecting structural variations as a prime candidate in future mechanistic studies of the biology of schizophrenia. By studying cells from patients, containing TAD-affecting mutations, future research may be able to develop new drugs or precision medicines that could potentially repair disrupted TADs, improving patient outcomes.

The data from the study will be combined with whole genome sequencing data from other similar studies to help confirm the results.

Read more: Nature Communications