A deep dive into the human genome opens the way for targeted schizophrenia treatments

Schizophrenia is a complex, heritable brain disorder that affects about one in 100 Australians. It produces symptoms of psychosis that can be controlled by drugs in many people, but almost a third do not respond. A drawback of medication is that it can produce unpleasant side effects, ranging from drowsiness and restlessness to weight gain and metabolic disorders.

‘The main treatments for psychiatric disorders haven’t changed a lot in the last 50 years, to be honest,’ says Professor Murray Cairns from the School of Biomedical Sciences and Pharmacy at the University of Newcastle. ‘Most of these drugs are focused on the symptoms.’

Cairns’ research focuses on understanding genetic factors and how they’re expressed in individuals, a field known as translational genomics. Recently, he was the recipient of a grant from NSW Health, to deep sequence the genomes of 500 participants from the Australian Schizophrenia Research Bank.

Cairns says this meant that ‘instead of collecting 30 million variants, typical for genetic studies, we got three billion variants across the genome’ – for just $1600 per person.

The results of that single project, which was part of the Sydney Genomics Collaborative initiative, opens the possibility of treatments that may target the underlying causes of schizophrenia, not just the symptoms.

Schizophrenia has been extremely difficult to tackle, because it’s a polygenic disorder. ‘It’s highly genetic, but the distribution of variants is very annoying,’ Cairns says. ‘You can’t just say, ‘this is the gene’ and then find a drug or gene therapy for that.’

The project offered a ‘fantastic opportunity’ to study individual genomes, looking for rare variants as well as common variants. ‘Common variants have a very tiny effect size and collectively they may have a big effect, but you also have people who have rare variants that have a much more potent effect,’ he says. ‘The only way to get to those rare variants is to do deep sequencing.’

Cairns thinks doctors are now closer to being able to calculate the polygenic risk score of each individual, which will be particularly helpful for groups at high risk of schizophrenia. ‘If there is a teenager displaying some symptoms and we determine they have a very high polygenic risk score for schizophrenia,’ then doctors can potentially offer early intervention.

Beyond that, the deep dive means Cairns and his colleagues can ‘take all those thousands of variants and look at how they aggregate into genes and into biological pathways,’ he says. The hope is when specific particular pathways are identified, ‘we can tailor a drug to that pathway’.

At present, anti-psychotic drugs primarily target dopamine, to control symptoms. But drugs that act on the underlying pathways could ameliorate or even cure the disease. Cairns says, for example, researchers have previously suggested that oxidative stress may play a role in some sufferers of schizophrenia, opening up the possibility that simple supplements could be of benefit. ‘Our hypothesis is that some people will benefit from N-acetylcysteine because they have low glutathione levels, but others won’t,’ Cairns explains. ‘We found there’s a genetic risk for a deficiency in that pathway.’

The research turned up other promising results, including the possibility that some people with schizophrenia have faulty retinoid signalling. ‘There had been a hypothesis that retinoids, or retinoic acid signalling was involved,’ Cairns says. ‘We showed that it was: we found both common polygenic variants and rare variants are associated. That suggests a potential drug target, because there are retinoids you can use clinically.’

Repurposing supplements is only one possibility. Cairns has developed an algorithm that can ‘spit out dozens of potential different drugs for each individual’.

The next step requires a bigger data set. Cairns is part of a global collaboration seeking rare variations of schizophrenia around the world. There is also a race to comb existing databases that hold information about drug and gene interaction, so the databases can identify potential drugs. ‘The next step is to do clinical trials,’ Cairns says.

It’s astonishing to think that a disease causing such havoc and misery might be relieved by simple supplements. And that’s only the start of benefits being offered by translational genomics.