FOR decades scientists have been trying to understand schizophrenia, a distressing disorder that afflicts one in a hundred people. Its destructive symptoms include hallucinations, delusions, muddled thoughts and changes in behaviour. The best drugs offer little more than the ability to target symptoms. There is presently no hope of a cure because its ultimate cause has long been a mystery.

Schizophrenia is known to run in families, so it has always been thought that genes might shed light on the origins of the disease. But the genetics have proved harder to unpick than anyone imagined. It is only now, 16 years after the human genome was first sequenced, that scientists have homed in on the relevant genes.

For more than five years researchers led by a group at the Broad Institute in Cambridge, Massachusetts, collected more than 100,000 DNA samples from around the world. They were looking for regions of the human genome that might be harbouring variants that increased the risk of schizophrenia. What they found implicated more than a hundred genes and provided a strong pointer towards a portion of the genome associated with infectious diseases. Many of these genes did not operate independently of each other, and further detective work revealed that the most important source of variation lay within a particular gene known as C4.

Steven McCarroll, of Harvard Medical School, and his colleagues involved in the study, report in Nature this week that particular forms of the C4 gene led to a greater risk of developing schizophrenia. What makes C4 hard to identify is that it comes in many different forms and has an intriguing function. The gene produces a protein known as a complement factor, which helps to tag pathogens for removal by the body’s immune system. In the brain, however, it appears to be tied to a developmental process known as “synaptic pruning”, in which neurons are continuously eliminated throughout childhood and into early adulthood.

In other words schizophrenics may be producing too much of a protein that creates a signal that synaptic connections should be removed. During late adolescence the brain undergoes widespread synaptic pruning, particularly in the cerebral cortex. This is also the age at which schizophrenia symptoms tend to begin.

David Goldstein, director of the Institute for Genomic Medicine at Columbia University, says he is persuaded by the research, but reckons it is important for the medical community to examine the study carefully because the region of the genome under discussion is hard to work on and is “stuffed full of genetic variation”. That makes it difficult to point to a single gene and say “it’s this”, he adds.

As to whether those with a family history of schizophrenia ought to have their genome sequenced to assess their susceptibility, Dr Goldstein is keen to point out that more work needs to be done on the risks that different forms of the genes bring. Moreover, other factors can be implicated in developing schizophrenia, ranging from taking psychoactive drugs to being exposed to viruses while in the womb.

Synaptic pruning is so crucial in brain development researchers wonder what other mental disorders might be tied to its aberrant activation or regulation. This study is bound to initiate a flurry of similar work. Alzheimer’s disease, for one, has been tied to, among other things, excessive destruction of synapses. And it is already believed that autistic individuals have a surplus of synapses in the brain, due to a slowdown in normal brain pruning. Indeed, the onset of autism often follows a period when there is a burst of synapse formation. One big step forward in schizophrenia research could have an enormous impact on the way other neurological disorders are viewed and treated.