A new genetic mutation in schizophrenia that blocks neuron communication in the brain may lead to novel treatment strategies and improve understanding of the mechanics of this disease.
Dr. Todd Lencz
The discovery of this new gene, PCDHA3, could enhance the development of genetic-risk calculators “that may help us understand vulnerability to schizophrenia in high-risk individuals and identify individuals with schizophrenia who have a greater risk for poor outcomes,” said Todd Lencz, PhD, a professor at the Feinstein Institutes for Medical Research in New York, and lead author of this research. Dr. Lencz and associates reported on this new finding in the journal Neuron.
Schizophrenia affects 20 million people worldwide. Previous research has identified the important role genes play in the disease, but isolating individual genes to better understand schizophrenia has proven to be a challenge. This is a very heterogeneous disorder, with many hundreds if not thousands of genes involved, Dr. Lencz explained in an interview. “It is very different from single-gene disorders like Huntington disease, for example. For this reason, we need very large sample sizes to find any one gene that seems to be common to many cases in a sample.”
Study focused on homogeneous population
To enhance the power of finding rare variants in a heterogeneous disease with large numbers of genes, Dr. Lencz and colleagues chose a homogeneous “founder” population, a cohort of Ashkenazi Jews, to examine genomes from schizophrenia patients and controls. “As we have reported in prior work over the last decade, the 10 million or so Ashkenazi Jews living worldwide today all are descended from just a few hundred people who lived approximately 750 years ago, and moved into Central and Eastern Europe,” said Dr. Lencz. The study included 786 cases of schizophrenia and 463 controls from this Ashkenazi population. This is considered to be an extremely small sample for a genetic study. However, because this population evolved from a few hundred individuals to a massive explosion in a historically short period of time, it had enhanced statistical power, said Dr. Lencz.
“We showed that just a few thousand Ashkenazi Jewish cases would have the statistical power of a regular population that was 5-10 times larger, from a genetic discovery perspective,” he added.
Search for ultrarare variants
The investigators used whole-genome sequencing to conduct their analysis, using public databases to filter out any variants that had been previously observed in healthy individuals worldwide. “We were looking for ultrarare variants that might have a very powerful effect on the disease,” Dr. Lencz said. Such individual mutations are very rarely seen in the general population.
Because of the disease’s ultraheterogeneity, it’s extremely unusual to find a recurrent, ultrarare variant. “In some ways, the genetics of schizophrenia is so complex that every patient worldwide is unique in the genetics that led to his or her disorder.” The goal was to find individual mutations that might be observed multiple times across the schizophrenia group, Dr. Lencz said.