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Thursday 31 July 2008

RAPID ROUNDUP: Genetics of schizophrenia (Nature) – experts respond

Embargo lifted at 3am AEST on Thursday 31 July 2008

Three separate international research teams have identified genetic variations associated with schizophrenia in Nature and Nature Genetics. Previously clear genetic associations have been difficult to establish.

Two of the studies, involving thousands of affected people, have independently identified two of the same variations and have confirmed a previously known deletion. The third study, which included Australian research from the Queensland Centre for Mental Health Research, has identified single nucleotide changes (where a single ‘letter’ in the code is altered) as independent risk factors for developing the disease.

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Professor John McGrath is Head of the Queensland Brain Institute’s Schizophrenia Group at the University of Queensland

“Schizophrenia is a poorly understood group of brain disorders that affects about 1 in 100 Australians. Individuals with this disorder have symptoms including hallucinations, delusions and problems with memory and planning.

The three studies published this week are the product of back-breaking work by international groups of researchers (including researchers based in Brisbane, Australia). Many thousands of people with schizophrenia have contributed to these studies. They provide clues to the types of genetic mistakes that are associated with an increased risk of schizophrenia.

If you think about the human genetic code as a huge instruction manual, some mistakes involve tiny, single letter typographical errors within the word. Another type of mistake may involve deleting a whole paragraph, or repeating a sentence twice.

The three papers published this week have reported findings that both of these types of genetic mutations increase the risk of schizophrenia. Unfortunately, the findings do not mean that we now have a ‘genetic test’ for schizophrenia. However, they provide powerful clues as to what type of mutations to look for, and where to look to find these mutations.”

Professor Vaughan Carr is CEO of the Schizophrenia Research Institute

“Copy number variation (CNV) is a hot new topic in relation to schizophrenia - it was discussed at the recent Schizophrenia International Research Society meeting in Venice (June). Studies of CNV represent a relatively new approach to the genetics of schizophrenia which has generally been disappointing in that linkage and association studies have turned up risk genes in some studies that have been poorly replicated in others. A recent meta-analysis of the leading candidate susceptibility genes revealed that none had a significant association with schizophrenia.

Hence the potential for excitement with these new studies in Nature.

The Stefansson et al study identified 2/3 deletions with quite large odds ratios implying that these confer high risk for schizophrenia. The results are based on a very large sample with good statistical power to detect differences between schizophrenia and controls (which has not been the case in many other studies where relatively small sample sizes have been a problem).

But it is important to note that these deletions account for only a small proportion of schizophrenia cases - many cases do not show these deletions. The CNVs identified are quite rare in the general population (and uncommon but not quite so rare in schizophrenia). Also, there is overlap with other conditions such as autism, various forms of mental retardation and other neurodevelopmental disorders including epilepsy and velocardiofacial syndrome (22q11 deletion). Thus it would be premature to consider these CNVs for genetic testing at the clinical and population levels (notwithstanding the very important replication of the 15q13.3 and 1q21.1 deletions in the International Schizophrenia Consortium study) as only a small minority of cases of schizophrenia would be positive, there is insufficient diagnostic specificity (ie, other neuropsychiatric/neurodevelopmental disorders appear to be associated with the same deletions) and, in terms of screening for prevention, we do not yet have the means for preventive intervention, so no benefit would flow from such testing. The real importance of the findings is that this is a significant step in unlocking the molecular basis for schizophrenia, at least some cases of schizophrenia, and thereby identifying potential new molecular treatments for the disorder.

The International Consortium study is exciting in that it replicates the two deletions with high odds ratios found in the Stefansson et al study. This study also points out that schizophrenia is associated with a greater burden (or number) of a variety of CNVs (which need to be studied in future research). Again, these authors point out that we don't yet know to what extent the risk of schizophrenia associated with these genomic deletions/duplications is specific for schizophrenia (unlikely in my view) or for more general neuropsychiatric disorders (more likely in my view).

Overall, the findings are more exciting from a scientific point of view than from a practical or clinical treatment point of view in that they point to a whole new domain of investigation that needs to be explored to try to unravel the causes of schizophrenia and other disorders of the nervous system, how these illnesses develop from these molecular foundations, and what environmental factors may bring these CNVs about and influence the development of different disorders such as schizophrenia and mental retardation from such common (ie. shared) foundations.”

Professor Pat McGorry is Executive Director of Orygen Youth Health

“We welcome this new and highly credible research which clearly links schizophrenia and related psychoses with a number of genetic risk factors. While we cannot estimate its impact on treatment for patients, any increased knowledge regarding etiology will eventually affect the quality of care we are able to offer. Obviously, more work needs to be done in this area to continue to identify and understand the genetic factors at play.”