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Ultra-Rare Genetic Variants in Protocadherin Gene Linked to Schizophrenia

NEW YORK — By focusing on a founder population with reduced genetic heterogeneity, researchers have uncovered rare genetic variants in the protocadherin gene that contribute to schizophrenia risk.

Schizophrenia, which is marked by delusion, hallucinations, and disorganized thoughts, affects about 1 percent of the global population. While studies have suggested that schizophrenia is highly heritable, genome-wide association studies have only uncovered common variants that together account for about a third of schizophrenia heritability.

This suggested to researchers led by Todd Lencz at the Feinstein Institutes for Medical Research that rare variants might contribute to schizophrenia heritability, though uncovering such variants has been difficult due to genetic heterogeneity and background variation rates. To overcome some of those hurdles, they focused their analysis on the Ashkenazi Jewish population, which is influenced by a strong founder effect about 750 years ago and has a more uniform genetic background.

As Lencz and his colleagues reported in the journal Neuron on Monday, they examined protein-altering rare variants found among Ashkenazi Jewish individuals with schizophrenia but not in controls. From this, they homed on a recurrent variant in the PCDHA3 gene that blocks the usual function of the protocadherin protein the gene encodes. This finding, the researchers added, could inform future treatment strategies.

"Other forms of evidence, such as examination of postmortem brain tissue from deceased patients with schizophrenia, have given some clues that protocadherins may be involved in schizophrenia," Lencz said in an email. "But this is the first genetic association study to identify specific ultra-rare variants associated with the illness."

The researchers analyzed the genomes of 786 individuals with schizophrenia and 463 controls from an Ashkenazi Jewish population and compared their missense or ultra-rare loss-of-function variants. In all, they identified 141 genes harboring variants only among cases. Included in these were three genes — SETD1A, TRIO, and XPO7 — that the Schizophrenia Exome Sequencing Meta-analysis (SCHEMA) consortium previously linked to the condition.

A gene set analysis of the 141 case-only genes found that they were enriched for known neurodevelopmental genes, synaptic genes, and cadherins.

A damaging ultra-rare mutation in the PCDHA3 gene cropped up multiple times in their schizophrenia cohort. The gene is part of the protocadherin gene cluster on chromosome 5 and is a member of the clustered protocadherin gene family. The family includes three gene clusters — α, β, and γ— that randomly form dimers that appear on the cell surface of neurons and interact with dimers on other neurites.

This variant, though, is situated in the EC5 domain that is needed for dimerization to occur. The researchers found that proteins with this alteration do not dimerize, cannot be detected at the cell surface, and instead are localized in the cytoplasm. This suggested to the researchers that the alteration could disrupt neural circuit formation.

This involvement of protocadherins in schizophrenia further points to potential treatment strategies, for example using protein kinase C. But Lencz noted that studies into that would take years. In the nearer term, he said he and his team are looking into how genetic alterations might serve as biomarkers to identify individuals with schizophrenia at increased risk of poor outcomes. In their study, individuals with the PCDHA3 variant tended to have an earlier age of disease onset or had treatment resistant disease that required clozapine therapy, he noted.

They also aim to expand their study by recruiting additional individuals in Israel as well as by applying their approach to other psychiatric disorders, according to Lencz.

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