deCODE-led Megastudy Finds New Genetic Clues to Causes of Schizophrenia
deCODE-led Megastudy Finds New Genetic Clues to Causes of Schizophrenia. Findings expand knowledge of the biology of the disease and provide potential new drug targets.
The largest study of the genetics of schizophrenia ever undertaken has revealed several new common single-letter variants in the sequence of the human genome (SNPs) linked to risk of the disease. The study, by a multinational consortium of scientists led by a team from deCODE genetics, analyzed the genomes of more than 50,000 patients and control participants from fourteen countries. It is published today in the online edition of Nature.
One of the SNPs is located near the neurogranin gene (NRGN) on chromosome 11. NRGN may be a candidate drug target, as it appears to play an important role in regulating both memory and cognition, processes that are often perturbed in schizophrenics. Another SNP is in the transcription factor 4 (TCF4) gene on chromosome 18, which is involved in brain development. Five of the SNPs are located very closely together in the Major Histocompatibility Complex, a region on chromosome 6 densely packed with genes regulating immune response. This lends support to previous research suggesting a possible environmental link between schizophrenia immune response. It has long been known, for example, that a disproportionately large number of schizophrenics are born in the winter and spring, when influenza rates are usually highest. All of the variants found in this study are very common 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. 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. One of the reasons this study was so successful is its unprecendented size. Pooling our resources has yielded spectacular results, which is what the participants from three continents hoped for. At the same time, this study underscores the fact that rare variants may well carry a significant part of the genetic risk of schizophrenia, so our next task is to use the ever more affordable sequencing technologies to find more of them,” said Kari Stefansson, CEO of deCODE and corresponding author on the paper.
In the first phase of the study, the deCODE-led SGENE consortium conducted a genome-wide scan of more than 300,000 SNPs in a total of 17,000 patients and controls from England, Finland, Germany, Iceland, Italy and Scotland. The 1500 SNPs with the best signal were then analysed in 11,000 patients and controls from the International Schizophrenia Consortium (ISC) and the European-American portion of the Molecular Genetics of Schizophrenia studies (MGS). Twenty-five SNPs with strong suggestive correlation were then followed up in more than 20,000 patients and controls from the Netherlands, Denmark, Germany, Hungary, Norway, Russia, Finland and Spain. Bringing together the results of different consortia established he association between the total of seven markers on chromosomes 6, 11, and 18 with increased risk of schizophrenia.
deCODE and all of the authors would like to thank the participants who took part in this study and made it possible. The SGENE consortium and its affiliated groups include 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 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. Follow up cohorts included those from Aarhus University, the National Serum Institute, and Bispebjerg and Glostrup hospitals, Denmark; Semmelweis University, Budapest; the Mental Health Research Center of the Russian Academy of Sciences; the Universities of Valencia and Santiago de Compostela, and the Hospital General Universitario Gregorio Marañón, Madrid, Spain; The Northern Finland Birth Cohort; Karolinska Institutet, Stockholm; Universities of Amsterdam, Utrecht and Maastricht, the Netherlands. The institutions comprising the ISC and MGS can be found in papers published concurrently with the present study in the online edition of Nature.
