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Protein-Truncating Variants Confer Schizophrenia Risk Across Human Populations

NEW YORK – Protein-truncating variants (PTVs) in genes constrained during evolution are an important genetic risk factor for schizophrenia across diverse populations, according to a new study by researchers at the Icahn School of Medicine at Mount Sinai and other places.

Schizophrenia, a severe mental illness that affects about 1 percent of the population, has genetic contributions from single nucleotide variants, copy number variants, and rare PTVs.

A study last year implicated rare coding variants in 10 genes in schizophrenia, however, that study and several others were focused mainly on people of European ancestry, even though the prevalence of the illness is equal across humans of different ancestral backgrounds.

"Now we find that these rare protein-truncating variants are a risk factor for schizophrenia across all human populations. So that's definitely a big finding," said co-author Alexander Charney, assistant professor in the departments of psychiatry and genetics at the Icahn School of Medicine.

For their study, published in Nature Genetics on Monday, Charney and his colleagues sequenced 161 genes that had previously been linked to schizophrenia in 11,580 cases and 10,555 controls from diverse ancestries, including 40 percent non-Europeans such as Africans and Asians.

The results showed that schizophrenia patients had higher rates of PTVs in genes that are evolutionarily conserved compared to the control group. 

Ten of the genes that harbored high levels of PTVs had previously been identified in a study conducted by the Schizophrenia Exome Sequencing Meta-Analysis (SCHEMA) Consortium in people of predominantly European ancestry. 

The study also identified two additional schizophrenia-related genes — SRRM2 and AKAP11 — with high levels of PTVs in schizophrenia cases. While SRRM2 has been previously linked to Alzheimer's disease and developmental disorders, AKAP11 has been shown to have a role in bipolar disorder.

"The two new genes are promising candidates for novel therapeutic development for schizophrenia," Charney said.

Meanwhile, the investigators found a third gene, PCLO, that was previously implicated in schizophrenia but has now been shown to be a shared risk gene for both schizophrenia and autism.

Although the study included populations of diverse ethnic backgrounds, a large proportion of the study participants had European ancestry. "While we do increase the diversity in this study, we still have a long way to go. Our study is not representative of the human population as a whole across the globe," Charney said.

As next steps, Charney wants to perform whole-exome sequencing to identify more genes that could increase schizophrenia risk.