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Rare Genetic Variation in 10 Genes Substantially Raise the Risk for Schizophrenia

Research Highlight

Schizophrenia is a serious mental illness that affects how a person thinks, feels, and behaves. People with schizophrenia may seem like they have lost touch with reality, which can be distressing for them and their families and friends. Although treatment is available, research suggests that as many as 30% of people with schizophrenia can be classified as treatment-resistant, indicating a critical need to identify new ways to treat this serious mental disorder. In one of the largest genetic studies of its kind researchers funded by the National Institute of Mental Health identified variations in 10 genes that significantly raise the risk for schizophrenia—information that could help identify new treatment targets.

Previous studies have investigated the genetic underpinnings of schizophrenia. In those studies, researchers found that the genetic risk for schizophrenia can be divided into:

  • Common genetic variation: These are variations that exist in a lot of people (e.g., more than 1 in every 100 people). Common variants in our genetic code may each carry a small risk individually (about 1% increase in risk), but these risks are additive.
  • Rare genetic variation: These variations exist in only a small number of individuals (e.g., 1 in 10,000 people).

A previous genetic study  of schizophrenia risk found common variation to be present in 270 different locations across the genome, primarily in areas that impact the regulation of genes. Other past genetic studies of schizophrenia identified ultra-rare genetic variations that confer substantial risk for this mental disorder, although more studies are needed to definitively confirm these findings.

Ultra-rare genetic variations occur infrequently, so researchers need large participant pools to find enough people with these genetic variations and examine how these variations impact schizophrenia risk. The NIMH-supported Schizophrenia Exome Sequencing Meta-analysis (SCHEMA) Consortium  was created to meet this need. The consortium is a global collaborative effort that brings together large amounts of data from many studies to help advance gene discovery.

In the current analysis, researchers used SCHEMA data to examine the coding sequences in the genome of 24,248 people with schizophrenia and 97,322 people without schizophrenia located across seven continents. The genetic analysis revealed 10 genes in which ultra-rare coding variants were significantly associated with schizophrenia. The variants identified in these genes included protein-truncating variants, which are genetic variations that damage or disrupt the proper translation of the gene, and missense variants , in which one of the building blocks of a gene is substituted with a different block, modifying the sequence of the protein and affecting its function.

The researchers found that the functions of the genes affected by the ultra-rare variants included those involved in:

  • The movement of charged particles into and out of cells and synaptic functioning (CACNA1G, GRIN2A, and GRIA3)
  • The control of transcription —the copying of instructions coded in DNA that are used to make proteins (SP4, RB1CC1, and SETD1A)
  • The movement and growth of neurons during development (TRIO)
  • The movement of substances into and out of the nucleus of cells (XPO7)
  • The modification of proteins by adding ubiquitin, which helps tell the cell where the protein should go (CUL1 and HERC1).

Ultra-rare genetic variations found in GRIN2A and GRIA3 provide support for the hypothesis that disruptions of the glutamatergic system—a system involved in communication between neurons—may lead to the development of schizophrenia, as GRIN2A and GRIA3 code for proteins used by glutamate receptors called NMDA and AMPA.

To better understand the biological processes affected by these rare coding variants, the researchers looked at ultra-rare coding variants in groups of genes involved in biological pathways —a series of actions that lead to the creation of a cellular product or changes in a cell. They found that ultra-rare coding variants were more common in 33 of these gene groups. These groups of genes were involved in biological processes such as communication between neurons, changes to chromatin  (the mixture of DNA and proteins found within cells), and regulating the movement of charged particles into and out of cells.

The study, one of the most extensive of its kind, sheds light on the genes that raise the risk of developing schizophrenia and the biological processes they are involved in, allowing for the identification of possible targets for treatment in the future.


Singh, T., Poterba, T., Curtis, D., Akil, H., Al Eissa, M., Barchas, J. D., Bass, N., Bigdeli, T. B., Breen, G., Bromet, E. J., Buckley, P. F., Bunney, W. E., Bybjerg-Grauholm, J., Byerley, W. F., Chapman, S. B., Chen, W. J., Churchhouse, C., Craddock, N., Cusick, C. M., DeLisi, L., … Daly, M. J. (2022). Rare coding variants in ten genes confer substantial risk for schizophrenia. Nature604(7906), 509–516. 


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