New Genetic Clues Unraveled for Schizophrenia
Neurology Today
2 October 2008;
Volume 8(19);
p 28-30
TALAN, JAMIE
Back to topARTICLE IN BRIEF
Two separate investigative groups reported that common variants in the genome confer risk for schizophrenia.
For more than 20 years, scientists have watched genetic links to schizophrenia appear - and disappear. Now, a new generation of genetic analyses - studies that cover genetic variation at the level of the whole genome - is proving its weight in identifying missing or duplicated pieces of the genome (copy number variations, or CNVs) that could increase risk for the disease.
Two large international teams have identified CNVs on chromosomes 1, 15 and 22 - although experts caution that it is still premature to know how these CNVs lead to risk and whether it will lead to a better understanding of schizophrenia.
These findings are all exciting but we don't have definite answers yet, said Thomas Lehner, PhD, chief of the NIH Genomics Research Branch and associate director of the Division of Neuroscience and Basic Behavioral Science at the National Institute of Mental Health. Dr. Lehner, who was not involved with the new studies, added: We need to take a comprehensive look at all the factors that contribute to schizophrenia. He noted that environmental and social factors are also involved in the disease.
Dr. Lehner and others believe that many pathways lead to the same phenotype.
The genetic findings were reported by two investigative groups in separate papers online in advance of the Sept. 11 print edition of Nature. One study comes from the International Schizophrenia Consortium (ISC), a collaboration between 12 institutes in the US, Europe, and Australia. The other is from the SGENE consortium comprising investigators from 18 institutions in Europe, the US, and China. Both teams found that rare deletions in genetic material are more common among patients with schizophrenia than in controls.
Figure. DR. SHAUN PURCELL: As a group, these [copy number variations] may be rare events, but individually these copy number variants may confer a large increased risk for schizophrenia.
RESULTS: GENETIC SCREENING
The ISC team collected DNA from 3,391 patients with schizophrenia and looked for CNVs.
The SGENE consortium, coordinated by Hreinn Stefánsson, PhD, of deCODE Genetics, looked for CNVs in DNA samples from more than 15,000 parents and their children who had a diagnosis of schizophrenia. After they identified certain CNVs, they turned to two different sets of schizophrenia patients, more than 5,000 genetic samples, to see whether the findings held up.
Figure. DR. DAVID ST. CLAIR: CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.
Both groups identified CNVs in three genes - chromosome 1,15, and 22 - that were more common among those with schizophrenia. (The SGENE group also found another CNV on chromosome 15.)
While these deletions were rare, found in around one percent in the general population, people with these rare CNVs had a three-fold and 15-fold higher risk of developing schizophrenia. The risk varied depending on the combination of deletions or duplications of the CNVs identified.
CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia, said David St. Clair, MD, PhD, of the University of Aberdeen in Scotland, one of the collaborators in the SGENE study.
These copy number variations are individually rare but because so many genes are expressed in the brain it is possible that eventually large numbers of them may be found to be responsible for a substantial proportion of cases of schizophrenia, said Dr. St. Clair. He added that advances in higher resolution technologies will eventually allow the identification of smaller microdeletions. The clinical importance is that they disrupt the function of one or more genes that are in the deleted region.
Dr. St. Clair and others explained that these microdeletions can be inherited or occur de novo (as new mutations) at conception, which is why someone can develop schizophrenia without any family history. That these mutations occur at a high rate in the population (about one percent) could explain why the incidence of schizophrenia remains at one percent, even though many patients do not go on to have children of their own.
The genes they linked to schizophrenia seem to have a variety of functions in brain development and neuronal signaling. These findings establish beyond a doubt that genetic abnormalities can cause schizophrenia and they explain why some cases seem sporadic because there is no family history, Dr. St. Clair added.
In an additional data set of 3,285 cases and 7,951 controls, the association was even stronger. Seven of 4,213 cases had one of the chromosome 15 deletions (15q13.3) compared to 8 of 39,800 controls. One of the genes in this region is the alpha-7 nicotinic receptor gene that the authors said is targeted to axons by neuregulin 1, and has been implicated in both schizophrenia and mental retardation.
Figure. DR. THOMAS LEHNER: These findings are all exciting but we don't have definite answers yet. We need to take a comprehensive look at all the factors that contribute to schizophrenia.
The International Schizophrenia Consortium (ISC) found genetic deletions associated with schizophrenia in chromosomes 1,15, and 22. As a group, these may be rare events, but individually these copy number variants may confer a large increased risk for schizophrenia, said Shaun Purcell, PhD, of Massachusetts General Hospital, who led the study.
He said that people with large deletions in these regions may have a ten-fold increased risk for schizophrenia. The largest effect was found on chromosome 22, with a 20-fold increased risk.
Dr. Lehner remains optimistically cautious about these findings. We are still missing the environment and other factors that influence how these genes are expressed. He suspects that complex psychiatric conditions, including schizophrenia, are disorders of genetic dysregulation that work in concert with environmental triggers.
We now have the technology and the large sample sizes. In a few years, we will have the answers.
