Two international teams of scientists working on independent studies have discovered that rare deletions and duplications in genetic material appear to occur in greater numbers in people who have schizophrenia.
The studies are published in the July 30th online issue of the journal Nature. One study is by the International Schizophrenia Consortium (ISC), a team of researchers from 12 institutions in Europe, the United States and Australia, and the other is by SGENE consortium, a team of researchers from 18 institutions across Europe, the United States and China.
1 in every 100 people is affected by schizophrenia at some point in their lives. It is a serious mental illness and around 70 per cent of cases are thought to have a genetic basis. However, like many psychatric disorders, it is not linked to one gene, but several, making it difficult to pin down.
Between them the two studies, which were essentially surveys that trawled the human genome, found that people missing certain sections of genetic material had up to 15 times the risk of developing schizophrenia compared to the general population.
The ISC researchers looked for a particular type of genetic error in 3,391 schizophrenia patients. The type of genetic error they investigated is called a copy number variation, where a particular section of genome is either missing or duplicated.
The SGENE researchers catalogued copy number variations between 15,000 parents and their children and then looked for them in two groups of schizophrenia patients, one with 1,433 people and the other with 3,285 people.
Both the ISC and the SGENE researchers found the same three copy number variations were linked to schizophrenia: one on chromosome 1, another on chromosome 15 and a third on chromosome 22. The one on chromosome 22 had alread been linked to schizophrenia before.
The SGENE team also found an extra copy number variation on chromosome 15, while the ISC team found that people with schizophrenia were more likely to have rare copy number variations than people who did not have the disease.
The frequency of these rare variations in the population at large is thought to be about 1 per cent, but the teams were not too sure about that. The risk of developing schizophrenia was estimated to be between 3 and 15 times greater than the general population for persons who had rare copy number variations, depending on the combination of deletions and duplications.
Understanding the genetics of schizophrenia and similar disorders relies heavily on large collaborative studies, because the variations are so rare. Kári Stefánsson, chief executive of Iceland based deCODE genetics, a member of the SGENE collaboration, said:
“We may have to identify a larger number of rare but high-risk variants to understand the genetic contribution to susceptibility.”
The coincidence of findings between the two independent groups, each using a different approach, has been welcomed by experts as an important step in understanding the genetic basis of schizophrenia, although there is still some way to go before the picture can be described as complete.
A member of the ISC team, Pamela Sklar of Harvard Medical School in Cambridge, Massachusetts, said the fact the two studies approached the problem from different angles using different methodologies was “fantastic for psychiatric genetics”.
Speaking about the ISC study in particular, R Thomas Insel, Director of the National Institutes for Mental Health in the US, said that by finding two previously unknown sites, the researchers tripled the number of genomic areas linked to schizophrenia:
“It also confirms in a large sample that unraveling the secrets of rare structural genetic variation may hold promise for improved diagnosis, treatment and prevention of such neuro-developmental disorders,” he added.
Meanwhile, Jonathan Flint from the Wellcome Trust Centre for Human Genetics at the University of Oxford, UK, said it was not going to be easy to convert these findings into a better understanding of the biology of schizophrenia.
However, this is the first time that studies involving large populations have shown links between the genetic deletions and duplications and schizonphrenia, which Stefánsson described as a “first component to a molecular test to aid in clinical diagnosis and intervention”.
Marjorie Wallace, chief executive of the UK mental-health charity SANE, said there was good reason to be cautious, because “for years we have seen many false positives in the search for the gene or genes”, and although the results were encouraging, “they are a long way from finding the causes, treatment and, above all, much needed prevention of psychotic illness.” However, she emphasized the importance of continuing this kind of research because:
“It is very important to find out who is at risk [of schizophrenia] so they can avoid triggers such as cannabis.”
“Large recurrent microdeletions associated with schizophrenia.”
Hreinn Stefansson, Dan Rujescu, Sven Cichon, et al.
Nature Advance online publication, 30 July 2008.
doi:10.1038/nature07229
“Rare chromosomal deletions and duplications increase risk of schizophrenia.”
The International Schizophrenia Consortium.
Nature advance online publication, 30 July 2008.
doi:10.1038/nature07239
Sources: Nature News, NIMH.
Written by: Catharine Paddock, PhD