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Dramatic genetic finding takes scientists a step closer to schizophrenia cause

Scientists have pinpointed a major trigger for schizophrenia in our molecular make-up that could explain why the disorder develops in adolescence. 

The study, published in the international journal Nature, found a huge spike in a single gene, C4, needed to prune away excess brain cell connections, dramatically increased a person's risk of developing schizophrenia.

Like pruning back the tangled branches of a hedge, synaptic pruning is part of the brain's natural development. The process helps thin out the overabundance of grey matter of a child's brain during adolescence to clear the neural pathways needed to develop more complex connections in adulthood. 

But in patients with schizophrenia with a spike in C4, this pruning switches into overdrive, shearing through too many synapses, causing an abnormal loss of brain matter, researchers found after analysing data from over 29,000 schizophrenia patients, 36,000 controls and 700 post-mortem brains from 22 countries.

The US study has been hailed as a watershed towards understanding the causes of the devastating mental illness that affects more than 280,000 Australians, with the potential for early detection and treatment unthinkable just a year ago.

"[It's] the most significant mechanistic study about schizophrenia ever," said Professor Steven Hyman, director of the Stanley Centre for Psychiatric Research, at the Broad Institute of MIT and Harvard, involved in the study.

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"I'm a crusty old curmudgeonly sceptic, but I'm almost giddy about these findings," he said of the research, led by a team at Harvard Medical School and Children's Hospital, Boston. 

The findings could explain three enduring mysteries that have dogged schizophrenia research for decades: the role of immune molecules (C4 is located in the chromosome 6 region involved in the immune system), the age of onset in young people, and the thinning of grey matter seen in autopsies of patients.

"It's a very exciting situation we're in now where we can see a clear association between a very microscopic process and a complex mental illness," said Professor of Psychiatry Jayashri Kulkarni at Monash University.

While most treatments for schizophrenia focus on the psychosis symptoms of the disorder, the study findings could explain what causes dementia-like symptoms in some schizophrenia patients that can be harder to treat, Professor Kulkarni said.

"The inadvertent over-pruning could be the cause of the cognitive impairment symptoms we see in some patients that become burnt out and have trouble with rapid processing, a lack of motivation to get out of bed, to even speak," she said.

"But gone are the days when we thought of schizophrenia as one homogenous illness caused by a single gene," she said, adding overzealous pruning may not fit with the florid symptoms including hallucinations and delusions, which are likely linked to overactive brain cell connections. 

The chair of psychiatry at the University of Melbourne, Professor David Castle, agreed the findings were an important step forward in understanding the causes of schizophrenia, but provided just one piece of the puzzle.

"At last count there were over 100 genes implicated in the development of schizophrenia," Professor Castle said.

"We are still very bad at identifying who is going to develop schizophrenia.

"We need to remember, it's not all down to genetics," he said, pointing to environmental risk factors and twin studies that found the identical sibling of a schizophrenia patient has only a 50/50 chance of developing the disorder. 

The potential for interventions based on genetic findings was still a long way off, Professor Castle said.

"Gene expression is so intricately involved in normal development that scientists need to be careful about trying to switch genes on and switch genes off," he said.

-with The Washington Post 

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