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Large-Scale Schizophrenia Exome Sequencing Study Identifies New Risk Genes

HOUSTON – A team led by researchers at the Broad Institute and Massachusetts General Hospital has identified new genes involved in schizophrenia by analyzing the exomes of almost 25,000 schizophrenia cases and 100,000 unaffected controls.

Last night at the American Society of Human Genetics annual meeting, TJ Singh, a postdoc at the Broad's Stanley Center for Psychiatric Research and at MGH, presented initial results from the project, called Schizophrenia Exome Sequencing Meta-Analysis Consortium, or SCHEMA.

Schizophrenia affects about 0.7 percent of the population and shortens life expectancy by 12 to 15 years. Though it has long been known to have a genetic component, little progress has been made in identifying new targets for therapy, Singh said. Also, while genome-wide association studies have already identified hundreds of risk loci for schizophrenia, it has been difficult to go from these associations to causal variants, specific genes involved, and the function of these genes.

Instead, Singh and his team decided to look at ultra-rare coding variants, which occur with much lower frequency but also have a greater effect size. In order to have sufficient power to find these types of variants, they needed to look at the exomes of a very large number of cases and controls.

SCHEMA started in August of 2017 and has recruited schizophrenia patients and controls from several populations, including those with European, Latin American, East Asian, Ashkenazi Jewish, and African American ancestry, though the majority have a European background. So far, it has analyzed the exomes of 24,248 cases and 97,322 controls, and found de novo mutations in 3,444 parent-child trios.

Singh said that because the targeted sequencing methods used were not identical, the researchers needed to develop quality-control methods to account for those differences.

So far, the team has identified 10 genes that confer substantial risk for schizophrenia, and 34 genes that are significant, and has made its results available in a browser. Two of the top 10 genes, GRIN2A and GRIA3, encode glutamate receptor subunits, supporting the hypothesis that diminished function of the glutamatergic system is involved in the pathogenesis of schizophrenia.

The researchers also found that both GRIN2A and SP4, which encodes a transcription factor, reside in loci that had already been implicated in schizophrenia by GWAS.

They compared these risk genes to genes implicated in other diseases, in particular neurodevelopmental delay, autism spectrum disorders, and intellectual disability, and found that there was significant overlap with autism. As such, it appears that the schizophrenia risk genes are more relevant to later-onset psychiatric disorders than to those with an early onset.

While there is not complete overlap between the schizophrenia genes identified by exome sequencing and the genetic loci found by GWAS, some of the rare variants can be useful to fine-map GWAS loci and prioritize genes in them, Singh said.

Even though the 10 genes the researchers identified are only mutated in about 5 percent of the schizophrenia cases they analyzed, the results are helpful to explore shared biology that underlies both common and ultra-rare variation in schizophrenia, he said. In addition, the researchers expect to find more rare schizophrenia variants as they analyze more cases.