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Redefining the diagnosis of psychiatric disorders

For world mental health day, Professor Sir Michael Owen, Director of the MRC Centre for Neuropsychiatric Genetics and Genomics, describes how genetics is changing the way we study psychiatric disorders – and our approach to biomedical research as a whole.  

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Image copyright: Mike Owen

We’re learning more and more about the genetics and biology behind psychiatric disorders, and one of the things this is telling us is that we need better diagnostic approaches.

In psychiatry we use diagnostic categories such as ‘schizophrenia’, based on clinical knowledge, to define sets of signs and symptoms in the clinic. This gives us an idea of what course the condition will take and its outcome. But these categories need to be more precise so the advances in understanding can be translated into better treatments.

Shared symptoms

Many psychiatric disorders share common symptoms and this can complicate diagnosis. Psychosis, for example, is a very important component of schizophrenia. But psychotic symptoms, such as delusions and hallucinations, can vary in severity and be found in people who are otherwise well. They are frequently seen in other psychiatric disorders, including bipolar disorder and can also occur in neurodevelopmental disorders like autism and intellectual disability.

Schizophrenia is caused by a massive number of small, inherited genetic effects that combine together. My research focuses on identifying genes associated with schizophrenia and using that knowledge to understand the underlying biology.

It’s taken a long time to get where we are today because the genetics are so complicated. But we’ve made huge progress, and I think that genetics will help us redefine the way we classify, define and treat psychiatric disorders.

Digging deeper

By collecting and analysing the genetic data of tens of thousands of people we’ve identified over 100 genes, or genetic regions, which contain differences in the genetic code – known as ‘risk alleles’. These risk alleles are significantly more common in patients with schizophrenia than people without a schizophrenia diagnosis. To put this work into perspective, eight years ago we had not yet discovered any genes linked to schizophrenia.

With our recently-awarded, five-year MRC programme grant, we’re ramping up the number of people in our studies. We plan to sequence all the genes of another 6,000 patients and combine that with a similar number of samples sequenced elsewhere.

This will allow us to identify important groups, or networks, of genes, as well as individual genes, conferring risk. We also plan to look at the genetic data in combination with other data, including clinical and imaging data, to discover new ways of grouping patients who might respond to specific treatments. This is an approach known as stratified medicine.

From genes to cells

Schizophrenia is caused partly by rare gene mutations that can substantially increase someone’s risk of developing the disorder. Some are small deletions or duplications of chromosomal regions, called ‘copy number variants’. Others are mistakes in a single letter of our genetic code, known as ‘point mutations’.

Once we’ve identified rare mutations, we can then grow brain cells carrying these disease-causing mutations. We can simulate the neural networks of the brain using lab-grown brain cells. The cells grow in a dish and connect up with each other to form networks. They synchronise their electrical activity, like real brain cells, allowing us to look for patterns of abnormality. In the future we hope this system will help us screen new treatments.

Scaling up

The challenge with studying rare gene mutations is that they are, by definition, very rare. So we need large numbers of samples to show that they are statistically more common in patients compared with people who do not have the disorder.

This has been a huge change right across genomics. Meaningful results now rely on people pooling their resources, establishing international consortia and scaling up the size of studies. A lot of our research collaborations are now international. Open science – making data publically available – means it’s possible for groups all over the world to participate.

Hopefully this will inspire more people trained in data-driven approaches to join the field. But if you’re a statistician analysing somebody else’s data, how do you get deserved credit for your contribution? These are all important issues for the scientific community to address, so that we can maximise the huge potential of genetics and improve the diagnosis and treatment of psychiatric disorders.

As told to Isabel Baker

Read more about the Open Science movement.

Access the Concordat on Open Research Data launched by the research councils, alongside three other leading UK organisations. Read MRC guidance for data sharing and open access.

Find out more about MRC-funded mental health research.

 

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