Rare gene found in five cases
Dr. Lencz and colleagues accomplished this with their unique Ashkenazi Jewish population. “We identified one particular mutation that was repeatedly observed in our cases that has not been observed in healthy individuals that we’re aware of,” he said. The PCDHA3 mutation was identified in 3 out of the 786 schizophrenia cases.
In another dataset, they examined from the Schizophrenia Exome Sequencing Meta-analysis (SCHEMA) consortium, they found it two additional times, bringing the total to five cases. SCHEMA is a large international consortium of genetics studies in schizophrenia that contains thousands of cases and controls, some of which are Ashkenazi Jewish cases.
“Importantly, the mutation was not observed in any controls, in either our Ashkenazi dataset, the SCHEMA dataset, or more than 100,000 other controls reported in several publicly available genetics databases,” Dr. Lencz said.
How the gene leads to schizophrenia
PCDHA3 derives from the protocadherin gene family, which generates a unique bar code that enables neurons to recognize and communicate with other neurons. This communication creates a scaffolding of sorts that enables normal brain function. Dr. Lencz and colleagues discovered that the PCDHA3 variant blocks this normal protocadherin function.
Among the 786 cases, the investigators found several other genes in the broad cadherin family that had implications in schizophrenia development.
Much of the genetics of schizophrenia in recent years has focused on the synapse as the point of abnormality underlying the disorder. “We think our paper demonstrates in multiple ways the synaptic scaffolding role the cadherins superfamily of genes play in schizophrenia pathophysiology. The discovery of the PCDHA3 variant adds a level of detail and resolution to this process, pointing researchers toward a specific aspect of synaptic formation that may be aberrant. “So the hope is we’re not just learning about these five individuals and their synapses. This result is perhaps telling us to look very carefully at this aspect of synaptic formation.”
Implications for clinical practice
Dr. Lencz and colleagues plan to expand upon and enhance their existing Ashkenazi sample to take advantage of the founder effect in this population. “Of course, there are many large-scale efforts to recruit ethnically diverse patients with schizophrenia to study around the world. We encourage that. Our expectation is that the biology is not in any way unique to Ashkenazi individuals. This is just the approach we took to enhance our power,” he said.
The PCDHA3 discovery won’t have an immediate impact on clinical practice. In the longer term, “we are aware of certain pharmacologic approaches that might be able to manipulate the cadherins. That would be a worthy focus for future research,” Dr. Lencz said.
Additional studies will be critical to see how current medications in schizophrenia treatment could mitigate and improve any changes caused by this genetic mutation, noted Anthony T. Ng, MD, who was not involved with the study. More specifically, studies would help assess the impact of a schizophrenia patient with this mutation in areas of functioning, “so that psychosocial and rehabilitation treatment models of schizophrenia can provide more targeted treatment,” said Dr. Ng, medical director of community services and director of neuromodulation services at Northern Light Acadia Hospital in Bangor, Maine.
The work of Dr. Lencz and associates is significant in that “it started to identify a very specific genetic change that can help focus treatment of schizophrenia,” Dr. Ng said.
Neither Dr. Lencz nor his associates had any conflicts of interest. Dr. Ng had no disclosures.