EU-funded study reveals schizophrenia triggers

An international team of researchers has pieced together the puzzle of the genetics of schizophrenia. Published in the journal Nature, their findings bring to light a number of new 'common single-letter variants' in the sequence of the human genome linked to disease risk.

The results are part of the SGENE (A large scale genome-wide association study of schizophrenia addressing variation in expressivity and contribution from environmental factors) project, funded under the 'Life sciences, genomics and biotechnology for health' Thematic area of the EU's Sixth Framework Programme (FP6). Due to end in October 2009, SGENE has received EUR 2.5 million in financial support. The project partners are seeking to identify genetic variants associated with schizophrenia, and to assess their interactions with environmental factors that might contribute to the pathogenesis of this disease.

For this study, the consortium, led by the Iceland-based pharmaceuticals group deCODE genetics, evaluated the genomes of over 50,000 patients and control subjects from 14 nations.

Over 300,000 single-nucleotide polymorphisms (SNPs) were scanned in the initial phase of the study. (An SNP is a variation in a DNA sequence that happens when a single nucleotide in the genome is different between members of a species.) A total of 17,000 patients and control subjects from Finland, Germany, Iceland, Italy and the UK were assessed. The 1,500 SNPs with the best 'signal' were evaluated in 11,000 patients and controls from the International Schizophrenia Consortium (ISC) and the European-American section of the Molecular Genetics of Schizophrenia (MGS) studies.

The researchers followed up 25 SNPs with strong suggestive correlation in more than 20,000 patients and controls from Denmark, Finland, Germany, Hungary, the Netherlands, Norway, Russia and Spain.

According to the researchers, one of the SNPs is located near the neurogranin gene (NRGN) on chromosome 11. Based on the results, NRGN has potential as a candidate drug target because is seems to be a key component for memory and cognition regulation. Researchers already recognise how the processes of memory and cognition are disturbed in people suffering from schizophrenia.

The study also found that another SNP is in the transcription factor 4 (TCF4) gene on chromosome 18 and contributes to the development of the human brain.

The researchers noted that five of the SNPs are found in the Major Histocompatibility Complex (MHC), the most gene-dense region of the mammalian genome. The MHC plays a major role in the immune, autoimmune and reproductive systems.

The outcome of the study shows an association between the total 7 markers on chromosomes 6, 11 and 18 with a higher risk of schizophrenia.

This finding adds weight to past studies that hinted at a possible environmental link between schizophrenia immune response. Researchers in this field have long recognised that a disproportionately large number of schizophrenics are born in the winter and spring - two seasons that are plagued with higher rates of influenza.

The variants identified in this study are very common, said the researchers, and each is associated with a modest increase in risk.

"Genetics offers a unique window for better understanding diseases like schizophrenia because the brain and cognition are so little understood and so difficult to study," explained co-author Dr Kari Stefansson, CEO of deCODE genetics.

"Discoveries such as these are crucial for teasing out the biology of the disease and making it possible for us to begin to develop drugs targeting the underlying causes and not just the symptoms of the disease," he added. "One of the reasons this study was so successful is its unprecedented size. Pooling our resources has yielded spectacular results, which is what the participants from three continents hoped for."

Dr Stefansson highlighted the fact that "rare variants may well carry a significant part of the genetic risk of schizophrenia." The research team now plans to use more affordable sequencing tools to find more of them, he added.

SGENE members include the Genetics Research Centre GmbH in Germany, the Landspitali University Hospital in Iceland, the National Public Health Institute in Finland and King's College London in the UK.

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