It has long been established that schizophrenia is a heritable disorder, often running in families across generations with lifetime risk increased in twins of those affected. However, this complex mental disorder has remained a gargantuan mountain to climb for researchers – despite consistent research into the area, pinning down genes that are even associated with schizophrenia has proved tricky.
Schizophrenia shows something called "genetic heterogeneity", which is a long way of saying that multiple genetic abnormalities produce a similar outcome. Heterogenous disorders are extremely hard to study, as there is not one sole cause, and creating animal models of them is often a guessing game – Alzheimer's disease research suffers from this issue greatly.
In a study recently published in the journal Neuron, researchers from The Feinstein Institutes for Medical Research and Columbia University claim to have found a new variant that is strongly linked with schizophrenia, highlighting a new mechanism by which the variant may cause disease. Their findings may lead to a new avenue of research to combat a disorder that affects 2.6 million adults in the USA.
The discovery was aided by veering away from the standard procedure of genome studies, instead choosing to use a founder population of Ashkenazi Jewish people. Founder populations are communities of people that began from very few members, meaning their genetic diversity is small. Using founder populations make genetic studies significantly easier, as the majority of people with a disease will likely have the same mutation that causes it, making it particularly useful in studying schizophrenia.
Lencz and colleagues took a sample of 786 schizophrenia patients and 463 controls, analyzing their genomes for new variants that may play a role in the disease. After scanning for previously-identified risk factor genes, the schizophrenic patients showed mutations in an array of genes previously identified, reinforcing existing data. However, they also discovered a new, single mutation in the patients. The mutation involved a single nucleotide change in a gene called PCDHA3, or Protocadherin Alpha 3, which is thought to be involved with the creation of cell-to-cell connections in the brain. The mutation directly blocks the action of this protocadherin, identifying a possible mechanism by which schizophrenia symptoms arise.
“In addition to our primary findings regarding PCDHA3 and related genes, we were able – due to the unique characteristics of the Ashkenazi population – to replicate several prior findings in schizophrenia despite relatively small sample sizes,” said Dr Lencz, professor in the Institute of Behavioral Science at the Feinstein Institutes, in an emailed statement.
“In our study, we demonstrated this population represents a smart, cost-effective strategy for identifying disease-related genes. Our findings allow us to zero in on a novel aspect of brain development and function in our quest to develop new treatments for schizophrenia.”
This is a major advance in the study of schizophrenia, which until now has failed to find therapeutic options for the disease. Current treatments involve care programs, which are about managing the disorder, and antipsychotics, which work towards reducing the symptoms of acute schizophrenia episodes. However, no therapies have made headway in treating the underlying causes.
Of course, no study is without limitations and this is no exception. The sample size is inherently small for a genetic study, and the isolated population may or may not be representative of the wider population. Larger studies will certainly be needed to expand on the lead that Dr Lencz and his colleagues have started.
