New Schizophrenia Genes Identified

Scientists have identified two new genes linked to schizophrenia and discovered that a third gene previously known to be involved in the disorder may also play a role in autism.

The genes were identified through a meta-analysis comparing gene sequences of 35,828 people with schizophrenia to 107,877 people without the condition.

The study builds on a report published last year that identified 10 genes with rare variants that are directly tied to schizophrenia risk. But that study, like most prior genetic analyses on psychiatric illnesses, was done on the DNA from people of European ancestry.

About 40% of the genetic samples included in this new work came from people of non-European ancestry, which researchers say makes it the most ethnically diverse schizophrenia genetics study to date.

Based on the findings, researchers concluded that the schizophrenia risk conferred by the rare genetic variants found on the new genes they discovered and on those previously identified is conserved across ethnicities.

The new genes, SRRM2 and AKAP11, contain rare protein-truncating variants (PTVs) that investigators say could be the cause of schizophrenia in some patients. The results could have significant implications for drug development.

Dr Alexander Charney

“It’s not curing the illness, but it is taking us a step closer so that we’re able to say that this may be the cause of the illness in a particular patient,” senior investigator Alexander Charney, MD, PhD, associate professor of psychiatry, genetics and genomic sciences, neuroscience and neurosurgery, at Icahn School of Medicine at Mount Sinai, New York City, told Medscape Medical News.

The findings were published online March 13 in Nature Genetics.

Schizophrenia’s Genetic Architecture

Prior studies suggest the genetic architecture of schizophrenia may be influenced by common single-nucleotide polymorphisms, copy number variants and rare PTVs.

Investigators note that rare PTVs are important because they can link disease risk directly to individual genes. But identifying the PTVs and the genes that harbor them requires large patient cohorts, far bigger than any single institution can provide.

Charney and other researchers are part of the Psychiatric Genomics Consortium, a collaboration of researchers from hundreds of institutions around the world established in 2007 to create large cohorts for genetic studies of psychiatric disease.

For this study, investigators sequenced a new cohort of 11,580 schizophrenia cases and 10,555 controls of diverse ancestries. The analysis showed that the findings previously established in predominantly European cohorts extended to non-European populations.

They then conducted a meta-analysis of the new cohort combined with datasets from earlier studies, creating a pooled sample of 35,828 cases and 107,877 controls.

This meta-analysis revealed two new genes linked to schizophrenia, SRRM2 and AKAP11. The third gene flagged in the study, PCLO, was previously implicated in schizophrenia but is now identified as having a shared risk for schizophrenia and autism.

The rare PVTs on the 12 genes identified so far through this type of study are probably only involved in a small fraction of schizophrenia cases, Charney acknowledged. However, the discovery could lead to new treatments that could benefit all patients with the disease, he added.

“There are multiple pathways to psychosis and there’s also multiple pathways to treat psychosis,” Charney said. “There’s reason to believe if you can find a mechanism by which a human being could develop a psychosis, then reversing that mechanism could help a lot of people who have psychosis for another reason.”

Importance of Diverse Cohorts

Commenting on the findings for Medscape Medical News, Jennifer Gladys Mulle, associate professor of psychiatry at the Robert Wood Johnson Medical School at Rutgers University, Piscataway, New Jersey, noted that while genetic discoveries have led to new therapies in other medical conditions, that has not been the case with schizophrenia.

Jennifer Gladys Mulle

“In other disorders, having genetic findings have really opened a window into the molecular mechanisms, which has allowed us to develop pharmaceuticals and understand the disease process better,” said Mulle, who was not part of this study. “But because we haven’t had that in schizophrenia, it’s really held us back. Having genetic variants associated with schizophrenia may really help us understand the mechanism.”

The inclusion of diverse populations is also a key contribution of this study, Mulle added.

“So far a lot of the work we’ve done in genetics has been on people of European ancestry,” Mulle said. “The fact that they have found results that are generalizable across multiple ethnicities really suggests that if we develop pharmaceutical agents based on these findings, it will help many people.”

More attention has been paid recently to a growing problem in the study of genetics of psychiatric disorders: More than 95% of participants in genome-wide association studies that seek to identify gene variants linked to disease are of European ancestry.

Charney and his colleagues had that in mind when they designed the study.

“We can’t get to a place where genetics is clinically useful if we don’t know the extent to which a particular observation that’s found in one population is also true for other populations,” Charney said.

The study was funded by the National Institutes of Health. Charney and Mulle report no relevant financial relationships.

Nature Gen. Published online March 13, 2023. Abstract.

Kelli Whitlock Burton is a reporter for Medscape Medical News covering psychiatry and neurology.

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