Researchers from Trinity College in Dublin, Ireland, have identified a risk gene mutation for schizophrenia and bipolar disorder that increases chances of developing the conditions by more than 10-fold. The team says they found this mutation is inherited from a distant but common European ancestor.
The international team, led by Prof. Aiden Corvin at Trinity's School of Medicine, says identifying this genetic mutation provides the medical community with insight into potential risk mechanisms for these disorders, the cause of which is poorly understood.
Results of their study are published in the journal Human Molecular Genetics.
Although treatments are available for schizophrenia and bipolar disorder, and evidence is increasingly suggesting these disorders share common genetic risk factors, the team says response to treatments varies and knowledge of the underlying biology has mostly eluded scientists.
Bipolar disorder affects around 4% of the world's population, and schizophrenia impacts around 51 million people around the world (about 1% of the world's population), the team says.
For their research, the investigators analyzed blood samples from over 1,564 Irish people with schizophrenia and 1,748 controls who did not have the disorder. They looked for small structural differences in the genome where material is either duplicated or deleted.
First author of the study Dr. Derek Morris, from the National University of Ireland (NUI), Galway, explains that when replication of a genome takes place, there can be small "editing" problems known as 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."
Carriers of genetic mutation share common European ancestor
Through their study, the researchers found five patients in which a gene - called Protein-Activated Kinase 7 (PAK7) - was duplicated. This duplication was not found in anyone in the control group, they note.
After looking for structural differences in the genomes of European subjects, the researchers found that a rare duplication in the PAK7 gene increased risks of developing schizophrenia or bipolar disorder 10-fold.
After identifying this genetic mutation in Irish people, the team extended their sample to include more than 25,000 people from Europe.
They confirmed that although this duplication is rare, it increases the risks of developing schizophrenia or bipolar disorder more than 10-fold.
Additionally, the team observed that in all cases, the duplications were very similar, suggesting the carriers share a single mutation that was inherited from a common European ancestor long ago.
Prof. Corvin says their findings show how gene discovery can provide new information on devastating disorders that are not well understood.
"Treatment in this area has advanced little in the last 40 years," he adds. "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."
According to the authors, the PAK7 gene family promotes growth and maintenance of brain connections in a pathway that is regulated by a previously known risk gene, called DISC1.
Both DISC1 and PAK7 interact with each other at the synapse level, the researchers say, which suggests that PAK signaling helps maintain synaptic networks - a mechanism that may play a role in development of schizophrenia and bipolar disorder.
Next step: how to reverse duplication interference with brain cell function
Prof. Corvin explains that their study shows the Irish population may be perfect for their gene discovery program, adding that the gene mutation likely came from a Northern European individual over 500 years ago.
"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," he says.
Regarding future research, Dr. Morris says:
"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."
A study published in late 2013 by Molecular Psychiatry suggested that a molecular process - called autophagy, which is a cell-maintenance mechanism - contributes to the development of schizophrenia.