Medical Scientists from Trinity College Dublin have identified a rare genetic mutation which increases the risk of developing schizophrenia or bipolar disorder more than ten-fold. Identification of this risk gene gives scientists a strong biological clue as to one of the potential risk mechanisms for these common disorders, which is important as the cause of these conditions is generally poorly understood.
The study, funded by the Wellcome Trust and Science Foundation Ireland, was recently published in the leading international peer reviewed journal Human Molecular Genetics. It was lead by Professor Aiden Corvin, Professor in Psychiatry at the School of Medicine, Trinity College Dublin and Head of the Psychosis Research Group at Trinity, in collaboration with colleagues at the University of Oxford. The study also included contributions from a broad network of collaborators in Europe and the US.
Schizophrenia or bipolar disorder affects about one in 50 Irish adults. Treatments are available, but response is variable and the underlying biology remains elusive. There is increasing evidence that these disorders share common genetic risk factors: identifying risk genes gives new insights into this biology and can inform new diagnostic and therapeutic approaches.
In this study the scientists examined blood samples from more than 1,564 Irish people with schizophrenia and 1,748 people without (the control group) to look for small structural variations where genetic material is duplicated or deleted in the genome. They identified five patients where part of a gene called Protein-Activated Kinase 7 (PAK7) was duplicated. Such duplications were not found in the control group.
Once the genetic mutation was identified in the Irish cases, the researchers were then able to specifically check for this mutation in schizophrenia and bipolar disorder samples from a much larger European sample (more than 25,000 people) which confirmed that this duplication, although rare, increased the risk of developing schizophrenia or bipolar disorder more than ten-fold. Significantly, the duplications appeared very similar in all cases and the authors found that the duplication carriers are all likely to share a single mutation inherited from a distant, common European ancestor.
Speaking about the significance of the study, lead author Professor Corvin said: “This finding demonstrates the power of gene discovery to provide new insights into poorly understood, but potentially devastating disorders. Treatment in this area has advanced little in the last forty years. Making progress in understanding the molecular mechanisms of disease gives me hope that new, effective treatments will emerge as has been the case in other branches of medicine, such as cancer treatment.”
Speaking about the biology of genetic mutations, first author of the study Dr Derek Morris, Lecturer at NUI Galway explained: “When a genome replicates, for example for egg or sperm formation, there can be very minor ‘editing’ problems called mutations. This is how diversity happens in biology and is like a typo in a book; it happens rarely and the context will determine how the ‘word’, or in our case a protein, is affected. In our PAK7 example about a third of the gene was replicated. For us the next steps will be to understand how this duplication interferes with brain cell function and to test how this might be reversed.”
Professor Corvin added: “The study also provides proof-of-principle that the Irish population may be advantageous for this type of gene discovery programme. The genetic mutation happened a long time ago and is carried by a very small group of patients. These people are all essentially very distantly related. It’s likely that the mutation came from some Northern European person, at least, but possibly more than 500 years ago. Because of the population history of Ireland we as a people are more closely related than in more diverse populations, so we were able to pick up on this mutation in the Irish descendants of this person. We believe that more is to be found in the Irish population and this will help us to reach a more general understanding about the nature of these disorders.”
The PAK7 gene family are known to promote the growth and maintenance of brain connections (synapses) in a pathway regulated by a previously identified risk gene (DISC1). The authors also confirmed that PAK7 and DISC1 interact with each other and that this interaction occurs at the level of the synapse, particularly in early adulthood. These findings suggest that PAK sigalling is involved in maintaining synaptic networks and that this mechanism may be important in the development of schizophenia and bipolar disorder.
The abstract is available here: https://hmg.oxfordjournals.org/content/early/2014/01/27/hmg.ddu025.abstract?sid=b154da81-07af-4a62-b0cb-e707ee2802e8