Genetic Insights into Schizophrenia from Rare Variants

Schizophrenia is a chronic brain disorder that is characterised by behavioural and cognitive symptoms, and could lead to a loss of touch with reality. This disorder is often not resolved by antipsychotic medications. Genetic studies have established the hereditary nature of schizophrenia. It has been revealed that not one but a large number of genes contribute to increasing the risk of developing schizophrenia. Some of these genetic variations are common with a lesser contribution to increasing liability, whereas other rare genetic variations are much more highly correlated to increasing the predisposition to schizophrenia.

Thus, identifying which genes or genetic sequences are at risk for schizophrenia can be highly beneficial, as they would not only provide us with new information and improve the understanding of the disorder as a whole, but also influence the development of future treatment for schizophrenia.

Common and Rare Genetic Variants Linked to Schizophrenia

The largest genome-wide association study has identified a total of 287 common locations in the genome which is linked to the liability or predisposition to schizophrenia. The common variants of schizophrenia are present in more than 1% of the population, and these have been found to explain 24% of the variance in schizophrenia liability in European populations. Since these variants are relatively common, they tend to have a smaller effect on the increase of predisposition to schizophrenia.

Apart from these, there are rare copy number variants (CNVs) and ultra-rare coding variants, which explain 5% of the schizophrenia liability. Researchers have been able to identify 13 such rare CNVs that act as schizophrenia risk factors. Rare coding variants (RCVs) that occur in the DNA sequence may collectively contribute to a higher risk of developing schizophrenia. These high-risk mutations have been found to be in a set of approximately 3000 genes. Moreover, 12 exome-wide significance genes that are linked to schizophrenia have been identified.

10 of these were by the SCHEMA (Schizophrenia Exome-Sequencing Meta-Analysis) consortium of 2022, and the other 2 were by the PGC (Psychiatric Genomics Consortiums). From these 12, 5 have also been found to be RCVs for other developmental disorders, indicating that there could be a genetic overlap. Hence, understanding these RCVS for schizophrenia can help in explaining the biological causes or risk factors of schizophrenia. Therefore, identifying and understanding more genes related to it can help better understand the neurobiology of schizophrenia.

Read More: New Tool to Detect Schizophrenia Through Brain Activity

Sample Characteristics and Sequencing Approach

Chick et al. (2025) sequenced 4,650 schizophrenia cases and 5,719 controls. They then met-analysed these with already published exome-wide sequencing data of 24,248 schizophrenia cases and 97,322 controls. Bringing the total dataset to 28,898 schizophrenia cases and 1,03,041 controls. Additionally, their dataset also included 3,444 trios, containing the person affected by schizophrenia and both of their biological parents. They wanted to understand which genes carry RCVs that would increase the risk of developing schizophrenia. For the same they wanted to understand which particular genes carry more RCVs in schizophrenia cases than in controls.

Identification of Novel and Confirmed Schizophrenia Risk Genes

In this research, eight genes associated with schizophrenia liability were identified. Two of them had previously been implicated as being associated with schizophrenia by other researchers. This study further confirmed and strengthened their association. These two genes were STAG1 and ZNF136. Additionally, six novel genes associated with schizophrenia were identified.

The association of these genes with schizophrenia was found to be moderate. These six genes were SLC6A1, KLC1, PCLO, ZMYND11, BSCL2, and CGREF. Additionally, the researchers also found that some of these genes that were found also had associations with RCVs of other disorders, such as developmental disorder, autism spectrum disorder, epilepsy, and bipolar disorder.

Implications of Rare Coding Variants in Schizophrenia and Related Disorders

The findings of this study indicate certain RCVs to be associated with a predisposition to schizophrenia. Identifying these genes helps understand biological regions and pathways involved in schizophrenia. Since it was found that certain genes associated with schizophrenia were also associated with other disorders, such as developmental disorder, autism spectrum disorder, epilepsy, and bipolar disorder, this indicates that there are certain shared or common underlying genetics among disorders.

Conclusion

The current study was crucial in identifying eight genes correlated with acting as risk factors for schizophrenia. Two of these genes had been implicated in previous studies, and their association was strengthened in the current research. The additional six risk genes associated with schizophrenia were newly identified.