A team of researchers have shown that schizophrenia and a disorder associated with autism and learning difficulties share a common biological pathway. This is one of the first times that researchers have uncovered genetic evidence for the underlying causes of schizophrenia.
The team found that a disruption of the gene TOP3B, an exceedingly rare occurrence in most parts of the world, is fairly common in a uniquely genetically distinct founder population from North-eastern Finland. In this population, which has grown in relative isolation for several centuries, the disruption of TOP3B is associated with an increased risk of schizophrenia as well as with impairment in intellectual function and learning.
Furthermore, the biochemical investigation of the protein encoded by the TOP3B gene allowed the researchers to gain first insight into the cellular processes that might be disturbed in the affected individuals.
Although the past two decades have revealed a wealth of information about the genetics of disease, we still know little about the biology behind schizophrenia. Many associations between schizophrenia and genetic risk factors have been reported, but only a very few can be considered schizophrenia susceptibility genes. This study uncovers an important biological pathway that appears to underlie schizophrenia and could contribute to the cognitive impairment that is an important component of this disorder.
"This is a tremendous discovery for our team; not only have we uncovered vital information about the biology behind schizophrenia, but we have also linked this same biological process to a disorder associated with learning difficulties," says Dr Aarno Palotie, lead author from the Wellcome Trust Sanger Institute, the Broad Institute of MIT and Harvard and the Institute for Molecular Medicine Finland. "Our findings offer great hope for future studies into the genetic basis of schizophrenia and other brain disorders, potentially finding new drug targets against them."
The North-eastern population of Finland has three times the frequency of schizophrenia compared to the national average in Finland, as well as a higher rate of intellectual impairment and learning difficulties. The team used data collected from this unique population to sift through genomic data for genetic deletions that may influence people's susceptibility to schizophrenia.
The team identified a rare genetic deletion affecting TOP3B in the North-eastern Finnish population that increases a person's susceptibility to schizophrenia two-fold and that also is associated with an increased frequency of other disorders of brain development such as intellectual impairment. They speculate that this deletion directly disrupts the TOP3B gene to cause its effects on the brain.
Having identified the link between TOP3B and schizophrenia, the researchers sought to understand why disrupting this gene might increase susceptibility to disease, and for this purpose they investigated the function of the protein that it encodes.
"Such an approach is only possible when researchers from different disciplines – in our case geneticists and biochemists team up," says Professor Utz Fischer, author from the University of Wurzburg. "Luckily, when we teamed up with the genetic team we had already worked on the TOP3B gene product for more than 10 years and hence had a good idea what this protein is doing".
TOP3B encodes a type of protein that typically helps the cell to unwind and wind DNA helices – essential to normal cell function. Quite unexpectedly for an enzyme of this class, however, TOP3B was found to act on messenger-RNA rather than DNA.
In their further biochemical investigation into TOP3B, the team found that the TOP3B protein interacts with a protein known as FMRP. The deactivation or disruption of this protein is responsible for Fragile X syndrome, a disorder associated with autism and learning difficulties, primarily in men.
Within the northern Finnish population, the team identified four people who did not have a functioning copy of the TOP3B gene. These four people were either diagnosed as having learning difficulties or as having schizophrenia, solidifying the evidence that this gene is important in these brain disorders and that they are biologically linked.
"These two disorders, schizophrenia and Fragile X syndrome, although they may seem drastically different, share key features, particularly the cognitive impairment that is frequently associated with both conditions," says Dr Nelson Freimer, author from UCLA. "So, it is not unexpected that they could share some of the same biological processes.
"What is fantastic about this study is that through investigations in an isolated corner of Finland we are contributing to concerted international efforts that are beginning to unravel the genetic root of schizophrenia, a debilitating disorder that affects so many people throughout the world."
Georg Stoll, Olli P H Pietiläinen, Bastian Linder, Jaana Suvisaari, Cornelia Brosi, William Hennah, Virpi Leppä, Minna Torniainen, Samuli Ripatti, Sirpa Ala-Mello, Oliver Plöttner, Karola Rehnström, Annamari Tuulio-Henriksson, Teppo Varilo, Jonna Tallila, Kati Kristiansson, Matti Isohanni, Jaakko Kaprio, Johan G Eriksson, Olli T Raitakari, Terho Lehtimäki, Marjo-Riitta Jarvelin, Veikko Salomaa, Matthew Hurles, Hreinn Stefansson, Leena Peltonen, Patrick F Sullivan, Tiina Paunio, Jouko Lönnqvist, Mark J Daly, Utz Fischer1, Nelson B Freimer & Aarno Palotie. (2013) 'Deletion of TOP3b, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders' Advanced online publication in Nature Neuroscience on 04 August. doi:10.1038/nn.3484
A full list of funding can be found on the paperParticipating Centres
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California, USA.
The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease. http://www.sanger.ac.uk
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests. http://www.wellcome.ac.uk
Contact detailsDon Powell Media Manager
Aileen Sheehy | EurekAlert!
Further reports about: > Broad Institute > DNA > Epidemiology > Genetics > Medical Wellness > Medicine > Molecular Target > Neuroscience > Parkinson’s Disease > Prevention > TOP3B > biological process > brain disorders > cellular process > chronic insomnia > cognitive impairment > developmental disorder > health services > learning difficulties > mental disorder > risk factor
Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery
20.01.2017 | GSI Helmholtzzentrum für Schwerionenforschung GmbH
Seeking structure with metagenome sequences
20.01.2017 | DOE/Joint Genome Institute
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
20.01.2017 | Awards Funding
20.01.2017 | Materials Sciences
20.01.2017 | Life Sciences