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Unlocking the neurobiology of schizophrenia

Priscilla Lynch reports on new research that is uncovering the neurobiology of schizophrenia

A team of scientists in the US Vanderbilt University Department of Molecular Physiology and Biophysics and the Vanderbilt Genetics Institute (VGI) has identified 104 high-risk genes for schizophrenia, using a unique computational framework they developed.

Their discovery, which was reported in April in the journal Nature Neuroscience, supports the view that schizophrenia is a developmental disease, which potentially can be detected and treated even before the onset of symptoms.

Symptoms of schizophrenia usually start between the ages of 16 and 30 years and genetics play a major role. While schizophrenia occurs in 1 per cent of the population, the risk rises sharply to 50 per cent for a person whose identical twin has the disease.

Recent genome-wide association studies (GWAS) have identified more than 100 loci, or fixed positions on different chromosomes, associated with schizophrenia. That may not be where high-risk genes are located, however. The loci could be regulating the activity of the genes at a distance.

To solve the problem, the paper’s senior author, Dr Bingshan Li, PhD, Associate Professor of Molecular Physiology and Biophysics and an investigator in the VGI, with first authors Dr Rui Chen, PhD, and postdoctoral research fellow Dr Quan Wang, PhD, developed a computational framework they called the ‘integrative risk genes selector’.

The framework pulled the top genes from previously reported loci based on their cumulative supporting evidence from multi-dimensional genomics data as well as gene networks.

The result was a list of 104 high-risk genes, some of which encode proteins targeted in other diseases by drugs already on the market.

“This framework opens the door for several research directions,” said Dr Li.

One direction is to determine whether drugs already approved for other, unrelated diseases could be repurposed to improve the treatment of schizophrenia. For example, one identified gene is suspected in the development of autism spectrum disorder.

“Schizophrenia and autism have shared genetics,” Dr Chen pointed out.

Another direction is to find in which cell types in the brain these genes are active along the development trajectory.

Ultimately, Dr Li said, “I think we’ll have a better understanding of how prenatally these genes predispose risk and that will give us a hint of how to potentially develop intervention strategies. It’s an ambitious goal… (but) by understanding the mechanism, drug development could be more targeted.”

Irish research

This latest study adds to major Irish co-led research published in Molecular Psychiatry in 2017, which highlighted the role of the brain’s white matter development in the development of schizophrenia.

The main focus of the worldwide study, co-led by Prof Gary Donohoe at the School of Psychology at NUI Galway with the University of Southern California, was to identify changes in white matter, often thought as the brain’s wiring system, relating to schizophrenia. Cumulative evidence has led to a ‘dysconnectivity’ hypothesis that schizophrenia may involve abnormal or inefficient communication between brain regions, due to disturbances in the underlying pattern of white matter. Until this large study, several small studies had tried to identify white matter changes with inconclusive results.

In an effort to overcome the problems of previous studies, researchers from around the world came together as part of the ‘ENIGMA consortium’ to carry out the first ever large-scale coordinated study of white matter microstructural differences in schizophrenia.

In an unprecedented sample of 4,322 individuals scanned across 29 cohorts from Australia, Asia, Europe, South Africa and North America, data from patients and controls were re-analysed in a manner that allowed greater power to identify changes across the brain. The study also determined if disease-related factors (including duration of illness, age at onset of schizophrenia, antipsychotic medication, smoking, and severity of positive and negative symptoms) were also associated with differences in white matter microstructure.

Using an approach known as diffusion tensor imaging, or DTI, the results from the study showed that throughout the brain, the so-called ‘white matter’ fibres which connect different brain regions are slightly altered, or frayed, making communication between different brain regions sub-optimal. While these differences were larger in some areas of the brain than others, an important finding from the study was that these changes were seen right across the brain and not just in one area. In schizophrenia, these changes are likely to help explain several clinical symptoms, such as, hallucinations and delusions, but also the cognitive difficulties that people experience and that strongly predict a level of disability.

Commenting on the study, Prof Donohoe said: “It’s almost 40 years since we had the first clues that schizophrenia was associated with changes in brain structure. What the ENIGMA consortium has achieved here is to provide definitive proof that these changes are not specific to any one area of the brain, but rather reflect subtle yet widespread changes throughout the brain. In terms of the idea that schizophrenia might be caused by a mis-wiring of the brain, this study provides unequivocal evidence that this is the case. The next steps will be to identify the individual genetics variants that lead to this mis-wiring.”

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