The three largest genetic schizophrenia studies to date have uncovered several ways in which changes to the genome may increase the risk of developing the condition.

The studies bring to light several common variations that increase the risk slightly, and rarer ones that raise it significantly, researchers say.

While previous studies have suggested several genes with roles in schizophrenia, small sample sizes gave these findings limited statistical significance.

Most recently, differences in copy number variations (CNVs) – chunks of genetic material that are either repeated or missing from the genome entirely – were identified between healthy and schizophrenic people . But the study was too small to implicate specific CNVs in causing the disease.


Quantity matters

Now, in the biggest study of its kind, the International Schizophrenia Consortium has collected further evidence about the role of CNVs in the condition.

The researchers examined the genomes of 3391 schizophrenics and found that they had around 15% more CNVs on average than the 3181 healthy controls.

This supports the idea that the sheer increase in CNVs alone could be a risk factor for schizophrenia.

Another study, led by David St Clair of the University of Aberdeen, UK, and deCODE genetics, Iceland, looked at 66 specific CNVs in 1400 schizophrenics and 33,000 healthy participants.

Missing regions

The team was able to identify several CNVs that are linked to a much higher risk of developing schizophrenia, but occur relatively rarely – in as few as one in 1000 schizophrenics.

They found three missing chromosome regions that raised the risk of developing schizophrenia by as much as 15 times. Importantly, two of these regions were also highlighted in the ISC study above, making it likely that these regions are a real risk factor.

Using yet a different approach, Michael O’Donovan of Cardiff University, UK, and colleagues looked for variations of single “letters” (SNPs) of the genetic code that were significantly more common in people with schizophrenia, occurring in as many as one in 10.

Common variant

In a study of more than 360,000 SNPs, they found three convincing associations in specific genes, one of which increases the risk by about 1%. The gene, called ZNF804A, may play a role in regulating the activity of other genes.

“The variation in that gene makes for a very small increase in risk, but it’s also very common,” O’Donovan says. “Together, the new studies show that many of us carry some risk genes for schizophrenia, but the people that have the illness simply carry more of them.”

“This is a provocative and important set of findings,” says Daniel Weinberger, at the National Institute of Mental Health in Bethesda, Maryland. But he adds that the rarity of the genetic variations means that the findings account for less than half a percent of schizophrenia cases.

“We don’t know yet if these results will translate to the other 99.5% of people with a schizophrenia diagnosis,” he says. “We’ll have to further interrogate these regions and see whether common variants within them predict the more common forms of the disorder.”

No simple test

There are likely to be many more genetic variants that are associated with schizophrenia coming to light – maybe as many as thousands, says St Clair. “I wouldn’t have said that even a year ago, but that’s the way it’s looking.”

That means that a simple genetic test is still a long way off. But both St Clair and O’Donovan believe that identifying some of the genes in the pathway – and where they can be found – is already a big step forward.

Dan Rujescu, a lead author on the deCODE study, likens the situation to that of Alzheimer’s disease.

“The findings of the rare Alzheimer’s mutations contributed hugely to the understanding of how Alzheimer’s works,” he says. “One of the hopes is that as more studies like these come out in the near future, we can also understand the physiology of schizophrenia.”

Journal references: Nature (DOI: 10.1038/nature07229);

Nature (DOI: 10.1038/nature07239);

Nature Genetics (DOI: 10.1038/ng.201)