Summary: The largest exome sequencing study of schizophrenia to date has identified eight new genes linked to the disease. Two genes, STAG1 and ZNF136, showed strong involvement, while six others showed a moderate association.
Notably, SLC6A1 and KLC1 were the first genes associated with schizophrenia risk to be specifically linked through missense variants, suggesting altered protein function. These findings shed light on the genetic mechanisms of schizophrenia and point to future diagnostic and therapeutic developments.
Key data
- Eight risk genes were identified: Two with strong evidence (STAG1, ZNF136) and six with moderate support.
- New mechanisms: SLC6A1 and KLC1 are linked only by missense mutations that alter the protein structure.
- Biological perspective: The results suggest that schizophrenia may be associated with changes in DNA organization and disruptions in GABA signaling.
Source: Cardiff University
In a groundbreaking genetic study, scientists have identified eight previously unknown genes associated with schizophrenia, offering fresh insights into the biological basis of the disorder. This discovery marks a significant step forward in understanding the complex genetic architecture that contributes to schizophrenia.
The findings emerged from the largest exome sequencing study ever conducted on the condition, involving data from tens of thousands of individuals. Researchers believe these newly identified genes could pave the way for more targeted treatments and improved diagnostic tools in the future.
This breakthrough, achieved by scientists at Cardiff University’s Centre for Neuropsychiatric Genetics and Genomics (CNGG), provides new information and improves the understanding and development of future treatments for schizophrenia.
The international study, published in Nature Communications, analyzed genetic data from 28,898 people with schizophrenia, 103,041 people without schizophrenia, and 3,444 affected families. The research team concentrated on identifying rare, high-impact mutations within protein-coding genes—genetic changes that can disrupt normal cellular function and are disproportionately found in individuals with schizophrenia. These mutations, though uncommon in the general population, may play a critical role in altering brain development and neural signaling pathways.
By targeting these severe variants, the study aimed to uncover deeper biological mechanisms that contribute to schizophrenia’s onset. This approach offers a more precise understanding of the disorder and opens the door to developing targeted therapies that address its genetic roots.
The study identified two genes (STAG1 and ZNF136) associated with schizophrenia, for which there is strong genetic evidence. Six other genes (SLC6A1, KLC1, PCLO, ZMYND11, BSCL2, and CGREF) were also associated with less evidence.
The study shows that SLC6A1 and KLC1 are the first schizophrenia risk genes linked exclusively through nonsense variants, a specific type of mutation that changes the amino acid sequence of a protein.
Sophie Chuck, a PhD candidate at Cardiff University, supported by Mental Health Research UK and the Fieldrose Charitable Trust, said: “These findings are illuminating because they suggest that schizophrenia may be linked to changes in the organisation of DNA within cells and also to disruption of communication between brain cells via a chemical called GABA.”
The research findings also support the hypothesis that schizophrenia and other neurodevelopmental disorders share common genetic causes. Four of the newly identified genes (STAG1, SLC6A1, ZMYND11, and CGREF1) have already been linked to autism, epilepsy, and developmental delays.
Dr Elliot Rees, from Cardiff University’s School of Medicine and lead author of the study, said: “It has long been known that rare genetic variants play a role in schizophrenia, but identifying the specific genes associated with these variants has been a major challenge.”
Because only a limited number of risk genes had been identified before this study, the researchers say the findings represent an important step in understanding the complex genetics of schizophrenia.
Although translating these genetic discoveries into treatments is a long-term goal, these findings offer new hope for the development of future drugs and targeted therapies.
Funding: This research was funded by the Medical Research Council, the UKRI Future Leaders Fellowship and Mental Health Research UK.
Abstract
Whole exome sequencing identifies schizophrenia risk genes.
Rare coding variants in many genes contribute to the predisposition to schizophrenia, but have been demonstrated at an exome-wide significance level in only 12 genes.
To increase the power of gene discovery, we analyzed exome sequence data for rare coding variants in a new sample of 4,650 schizophrenia cases and 5,719 controls and combined it with published sequence data from a total of 28,898 cases, 103,041 triband-controls, and 43,43, 43,041 controls.
We found associations with exome-wide significance for STAG1 and ZNF136, the first schizophrenia-associated gene in the SCHEMA study, with a false discovery rate of 5%.
The researchers also identified associations, at a 5% false discovery rate, for six genes, SLC6A1, PCLO, ZMYND11, BSCL2, KLC1, and CGREF1 that had not reached statistical significance in the earlier SCHEMA study. While these genes did not meet the strictest thresholds previously, their emergence in this analysis suggests they may still play a meaningful role in schizophrenia risk.
These findings highlight the value of expanding genetic studies to larger and more diverse datasets, as subtle but important signals can emerge with greater statistical power. Further research will be needed to confirm the involvement of these genes and to explore how their rare variants might influence brain function and contribute to the development of schizophrenia.
Of these genes, SLC6A1 and KLC1 are uniquely associated with deleterious missense mutations. STAG1, SLC6A1, ZMYND11, and CGREF1 also show rare coding variants in other developmental and psychiatric disorders. Furthermore, STAG1 and KLC1 share well-mapped distinct features in schizophrenia.
These findings provide insight into the neurobiology of schizophrenia and provide additional evidence that altered chromatin organization plays an etiological role.
