Findings may provide the foundation for a test to complement standard clinical diagnosis, potentially enabling earlier intervention and treatment
Reykjavik, ICELAND, July 30, 2008 – In a major paper published today in the online edition of the journal Nature, scientists from deCODE genetics (Nasdaq:DCGN) and the University of Iceland, along with academic colleagues from the deCODE-led European SGENE consortium, China and the United States, report the discovery of three rare deletions in the human genome that confer risk of schizophrenia. Such deletions are gaps in the normal sequence of the genome that can arise spontaneously during the recombination or reshuffling of the genome that takes place in the creation of sperm and eggs. The deletions reported in today’s study are located on chromosomes 1q21, 15q11 and 15q13, and confer, respectively, 3, 15 and 12 times greater than average risk of schizophrenia. These are the first such deletions to be associated with risk of mental illness using large sample sizes and validated across many populations. The substantial increase in risk they confer make them a valuable basis upon which to develop molecular diagnostic tests to complement standard clinical diagnosis. The study, ‘Large recurrent microdeletions associated with schizophrenia,’ will appear online today at www.nature.com.
“Schizophrenia is a disorder affecting thoughts and emotions. It is therefore a quintessentially human disease, but one that is little understood biologically and which is difficult to diagnose. These findings are important because they shed light on its causes and provide a first component to a molecular test to aid in clinical diagnosis and intervention. These discoveries also demonstrate one way in which we can use SNP-chips to find rarer genetic factors conferring risk of disease. In many disease areas we have had great success of late in identifying what these chips are best suited to find: common variants conferring relatively modest increases in risk. But we know that individuals with certain mental disorders such as schizophrenia tend to have few children, and thus that we may have to identify a larger number of rare but high risk variants to understand the genetic contribution to susceptibility. It is encouraging that our efforts to use SNP chips to detect rarer variations such as spontaneous deletions and duplications is now bearing fruit,” said Kari Stefansson, CEO of deCODE.
In the recent wave of discoveries of risk variants for common diseases, those associated with mental disorders such as schizophrenia, autism and others have been conspicuously absent. This phenomenon, and the fact that people with these disorders tend to have few children, suggest that rarer and perhaps spontaneously generated variants may account for a greater proportion of the disease burden in these conditions than in others. SNP-chips are not well suited to finding rare SNPs but can, with sufficiently large sample sizes, be used to identify deletions and duplications – known as copy number variations, or CNVs – which can also be carried by healthy individuals in one generation and contribute to risk of disease in the next.
In order to identify novel CNVs, deCODE first analyzed the genomes of a total of approximately 15,000 parents and offspring taking part in deCODE gene discovery programs and who had been genotyped with the more than 300,000 SNPs on the HumanHap300 chip. The deCODE team discovered 66 de novo CNVs, that is, CNVs present in the genomic DNA of the offspring but not in that of their parents. deCODE then tested these variants for association with schizophrenia in more than 1,400 schizophrenics and 33,000 control subjects. The deletions on chromosomes 1q21, 15q11 and 15q13 were suggestively associated with schizophrenia in this first phase, and then validated in 3,300 cases and 8,000 controls. The SGENE consortium is comprised of deCODE genetics, the National-University Hospital in Reykjavik, the University of Aberdeen, the Ravenscraig Hospital in Greenock, the Institute of Psychiatry at King’s College London, the National Public Health Institute in Helsinki, the Ludwig Maximilians University and GlaxoSmithKline’s Genetic Research Center in Munich. The SGENE affiliated groups taking part in the second phase of the project were the University of Copenhagen, the University of Oslo, the University of Heidelberg, the University of Bonn, the University Medical Center of Utrecht, Nijmegen Medical Center, the University of Verona, the Duke University Center for Population Genomics and Pharmacogenetics and the University of Sichuan, China.
deCODE and the SGENE consortium gratefully acknowledge the participation in this study of the thousands of patients, family members and control subjects from these eleven countries. This study was supported by the European Union through the SGENE consortium (www.SGENE.eu), by grants LSHM-CT-2006-037761 and PIAP-GA-2008-218251.
deCODE is a biopharmaceutical company applying its discoveries in human genetics to the development of diagnostics and drugs for common diseases. deCODE is a global leader in gene discovery — our population approach and resources have enabled us to isolate key genes contributing to major public health challenges from cardiovascular disease to cancer, genes that are providing us with drug targets rooted in the basic biology of disease. Through its CLIA-registered laboratory, deCODE is offering a growing range of DNA-based tests for gauging risk and empowering prevention of common diseases, including deCODE T2™ for type 2 diabetes; deCODE AF™ for atrial fibrillation and stroke; deCODE MI™ for heart attack; deCODE ProCa™ for prostate cancer; and deCODE Glaucoma™ for a major type of glaucoma. deCODE is delivering on the promise of the new genetics.SM Visit us on the web at www.decode.com; on our diagnostics website at www.decodediagnostics.com; and, for our pioneering personal genome analysis service, at www.decodeme.com.
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