Schizophrenia: A complex multi-system genetic disorder?

Leila Luheshi

23 July 2014

Schizophrenia is a highly debilitating psychiatric disorder that affects around 25 million people worldwide. While some drug treatments are available to manage the symptoms of schizophrenia, no curative or preventive interventions are currently available.  This is largely due to the inherent difficulties of research into the biological basis of a disease whose origin lies in the most structurally and functionally complex organ in the human body, the brain. The lack of a clear and detailed understanding of what happens within the brain, and indeed the rest of our body, to cause schizophrenia means it remains difficult to design effective therapies to prevent these processes from occurring.  Instead, patients are left with relatively non-specifically acting anti-psychotic drugs, which can be effective in ameliorating symptoms, but which are also accompanied by many unpleasant side effects.

A new study published today in Nature offers some of the most profound insights yet into the biological basis of schizophrenia, and offers tantalising hope that it may yet be possible to disentangle the complex web of genetic and environmental factors that contribute to this disease. Through genome wide analysis of over 100,000 people, separated into those with schizophrenia and those without, they have identified 83 previously unknown regions of the genome that contribute significantly to the risk of developing schizophrenia.

Analysing the genetic influences

The researchers looked more closely at these genomic regions implicated in schizophrenia to try and understand what role they might play in the disease and found that they included many genes with important known functions in the brain such as regulators of neuronal activity and development. Strikingly, they also found important links with genes whose main roles appear to be outside the brain, in particular a subset that are known to be involved in our immune responses. This finding is particularly intriguing as there is some epidemiological evidence to suggest that exposure to infection at key times during brain development might affect your risk of developing schizophrenia in later life.

While these findings open many important new avenues for research and potential therapeutic development, their impact on understanding and predicting risk of developing schizophrenia is less certain. Although the authors demonstrate that presence of particular variants in the affected genomic regions can be used to create a ‘risk score’ for schizophrenia, they caution that this score is far from being sufficiently accurate at this time to use in any population based screening or clinical diagnostic setting.

The value of genomics for neurodevelopmental disease

This study highlights some important wider questions about the value and utility of genomic information in managing neurodevelopmental diseases. The inherent complexity of the brain, with its millions of neurons forming trillions of connections with one another, means that whilst understanding the genetic basis of diseases such as schizophrenia might allow us in principle to target therapies to more relevant subset of neurons and types of neural activity, there will still be a huge amount of trial and error involved in find drugs or other approaches that treat the disease effectively and cause minimal unwanted side effects. Already we know that this complexity and high likelihood of failure is a disincentive for drug companies to undertake pharmaceutical development in psychiatric and neurological disease.

Furthermore, given that there is not as yet a way to intervene to either prevent or cure schizophrenia, the utility in using genomics as a basis to identify people at risk of schizophrenia or other neurodevelopmental disorders prior to onset of symptoms also remains unclear. As with late onset neurological disorders such as dementia, it is important to consider whether many of the ‘at risk’ population would wish to know their status, given the relatively limited opportunities to mitigate the disease when it occurs. On a more positive note, if (and it remains a big ‘if’) upon further investigation the role of immune activation in schizophrenia, hinted at by this latest study, becomes more established, this may point the way towards preventive interventions that could yet have a significant impact in reducing the incidence of this devastating disease.

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