March 28, 2023

Genetic link to depression and schizophrenia confirmed in UOW led study

International team finds gene expression link in patients with psychiatric disorders

An international team of scientists, led by University of Wollongong (UOW) researcher Dr Natalie Matosin, has confirmed a genetic association with severe psychiatric disorders such as depression and schizophrenia, which may change the face of therapeutic care.

The study, published in the latest edition of Acta Neuropathologica, brought together decades of evidence from around the globe suggesting that the FKBP5 gene may raise risk to mental illness in a subset of people.

Dr Matosin is Head of the Mental Illness and Disorders of Stress (MINDS) Lab at UOW’s Molecular Horizons. To undertake this project, she brought together a team of researchers from around the world including Melbourne, Germany, Canada, the USA, Iceland, Brazil and Sweden.

“The FKBP5 gene one of the very few genes in psychiatry with good evidence that it raises risk of developing a mental illness such as depression, schizophrenia, PTSD and anxiety,” Dr Matosin said.

“People who carry a specific form of this gene have a higher chance of developing a mental illness. But interestingly, the gene is only ‘activated’ if a person has been exposed to severe stress early in life.

“The protein produced by this gene is a key contributor in how everybody processes stress – when we are exposed to stress, we produce high levels of the FKBP5 protein, and then when the levels reach a threshold they signal back to turn off the stress response.

“Many people with mental illnesses have dysregulated stress responses and their brains have difficulty turning off the stress response. This suggests that FKBP5 is involved.”

The study looked at over 1000 human brain specimens from people that lived with a mental illness and had donated their brains to research. This enabled the researchers to closely study FKBP5 directly in the brain. This was the largest and most comprehensive study into FKBP5 in the brain to date.

“Most previous studies assessing FKBP5 have looked in animal models of stress, or in blood samples from patients. There have been other studies looking in the brain before, but they were only able to study a small number of specimens.

“The size of our study and being able to look directly in the human brain, were key features of our work because the brain is central to the development of symptoms and primarily where drugs are having an effect. While animals play a key role in medical research, there can be species differences.

“We looked at multiple areas of the cortex, the outer layer of the brain, and arguably one of the most complex parts of the brain. It's what makes us human. It is the part of the brain involved in higher cognitive functioning such as memory, learning, problem solving and decision making.”

The study looked at multiple areas of the cortex that serve slightly different functions to observe the pattern of expression of the FKBP5 gene across the cortex.

“We confirmed expression of the FKBP5 gene and its associated protein, were both elevated across in depression, bipolar disorder and schizophrenia. This is what we expected. The evidence has long suggested people with mental illnesses have elevated levels of FKBP5 directly in the brain.

“But what we ended up seeing consistently throughout the research was that there were much stronger increases in FKBP5 in people with schizophrenia.”

Using the suite of microscopes at UOW’s Molecular Horizons and cutting edge molecular techniques that allowed the researchers to look at the molecular makeup of single cells, the team were able to pinpoint effects to a specific type of neuron residing in the upper layers of the cortex. This presents a new treatment target in battling mental illnesses.

“With this new information and ability to pinpoint the effects of a gene to a specific type of neuron, it can help us to more carefully tailor new therapeutics.”

The research also has implications for the least treated symptom profiles of psychiatric disorders - the cognitive symptoms: the ability to learn, remember, reason, process information and pay attention.

“We’re leaning into the hypothesis that there's some disruption of cognition caused by FKBP5 and if we could bring down the levels of the gene it may improve the brain circuitry needed for cognitive function,” Dr Matosin said.

“We saw the changes to FKBP5 in the cortex, especially in the prefrontal cortex areas that have a significant role in cognitive function. This is important because these are the most debilitating symptoms that leave patients with a worse prognosis.”

Cognitive symptoms, such as impediment to learning and memory, result in the worst outcomes for patients. Currently none of the antipsychotics or secondary medications available treat cognitive function.

Dr Matosin is hopeful that this research will have far reaching implications for the way psychiatric disorders are treated, moving away from the need to trial different medications before an effective treatment is found.

“What we're trying to do is understand the biology, because if we can classify patients according to their biology, then the best way to treat their specific symptoms will be identifiable, and will one day alleviate the need to go through trial and error to find an effective treatment.”