A gene involved in managing the connections between brain cells appears to be associated with an increased risk of developing schizophrenia.
While previous research had shown that schizophrenia has a genetic component, this is the first time that a specific gene and biological pathway has been identified as contributing to the disease.
'Since schizophrenia was first described over a century ago, its underlying biology has been a black box, in part because it has been virtually impossible to model the disorder in cells or animals,' said Dr Steven McCarroll of Harvard Medical School, senior author on the study, which was published in Nature.
'The human genome is providing a powerful new way in to this disease. Understanding these genetic effects on risk is a way of prying open that black box, peering inside, and starting to see actual biological mechanisms.'
The researchers analysed genetic data from 28,799 schizophrenia cases and 35,986 controls, across 22 countries. Previous genome analysis had identified variation in chromosome 6 as increasing the risk of schizophrenia, but with no further clues as to which of the genes in this region might be a risk factor for the disease.
Basing their study on this chromosomal region, Dr McCarroll and his team focused on an unusual gene called complement component 4 (C4). Unlike most other genes, the type and number of copies of C4 varies between different people.
By using a novel technique to identify the type of C4 present in DNA, the researchers found that they could predict the behaviour of different types of C4 in people with and without schizophrenia. Particular variants, which cause an increased amount of C4 activity, appeared to increase the risk of developing schizophrenia by 27 to 50 percent.
In mice, C4 was found to have an important role in 'pruning' unnecessary synapses – the connections between neurons – in the brain. The greater the amount of C4 in the developing brain, the higher the number of synapses that were eliminated.
In humans, most synaptic pruning happens during adolescence and early adulthood – the same age at which the symptoms of schizophrenia most commonly present. This research proposes that a high level of C4 activity could result in the over-removal of cells in the brain, causing both the thinning of brain tissue and the cognitive symptoms observed in schizophrenia.
Speaking to the MIT Technology Review, Dr Steven Hyman, director of the Stanley Center for Psychiatric Research and a former director of the US National Institute of Mental Health, who was not an author on the study, said: '[This research] begins to suggest potential routes toward therapies.'
However, it is clear that the implications of these findings on future treatments are complex. 'It's not going to be an easy thing to tweak synaptic pruning because underpruning wouldn't be so good either,' said Dr Hyman.