Scientists Discover Eight New Schizophrenia Genes
Scientists Discover Eight New Schizophrenia Genes

Scientists Discover Eight New Schizophrenia Genes

Summary: The largest exome sequencing study of schizophrenia to date has discovered eight new genes associated with the disorder. Two genes, STAG1 and ZNF136, showed strong involvement, while six others showed moderate associations.

Surprisingly, SLC6A1 and KLC1 became the first schizophrenia risk genes to be specifically associated with missense variants, which show changes in protein function. These findings shed light on the genetic mechanisms of schizophrenia and point to future diagnostic and therapeutic developments.

Key facts

  • Eight risk genes were identified: Two with strong evidence (STAG1, ZNF136) and six with moderate support.
  • New mechanisms: SLC6A1 and KLC1 are linked only through missense variants, which 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

Researchers have discovered eight new genes linked to schizophrenia in the largest exome sequencing study of the disorder to date.

A groundbreaking study led by scientists at Cardiff University’s Centre for Neuropsychiatric Genetics and Genomics (CNGG) has significantly advanced our understanding of the genetic basis of schizophrenia. This international collaboration, recently published in Nature Communications, sheds light on the complex biological underpinnings of the condition and provides valuable insights for the future development of more targeted and effective treatments. The research marks a crucial step toward unraveling the intricate genetic architecture of schizophrenia, a severe mental illness that affects millions of people worldwide.

The study analyzed genetic data from a large and diverse cohort, including 28,898 individuals diagnosed with schizophrenia, 103,041 individuals without the condition, and 3,444 families affected by the illness. By focusing specifically on rare, disruptive mutations in protein-coding genes, the researchers aimed to identify genetic variations that contribute to the onset and development of schizophrenia. These rare mutations were found to be significantly more common in individuals with the illness, suggesting a strong link between these genetic disruptions and the disease’s manifestation.

Among the key findings, two genes STAG1 and ZNF136 emerged with strong genetic evidence linking them directly to schizophrenia. In addition to these, six other genes SLC6A1, KLC1, PCLO, ZMYND11, BSCL2, and CGREF were also associated with the disorder, albeit with less statistical certainty. These discoveries not only highlight new genetic risk factors but also open up potential avenues for further research into the biological mechanisms of schizophrenia. Ultimately, the study provides a more detailed genetic map of the disorder, offering hope for improved diagnosis, personalized treatment, and prevention strategies in the years to come.

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 funded by Mental Health Research UK and the Fieldrose Charitable Trust, emphasized the broader implications of the study’s findings. “These findings are informative because they suggest that schizophrenia may also be linked to changes in the organization of DNA within cells and disruptions in communication between brain cells using a chemical called GABA,” she explained. This points to the potential involvement of both genetic structure and neurotransmitter imbalances in the development of the disorder, offering new perspectives on how schizophrenia affects brain function at a molecular level.

The study identified SLC6A1 and KLC1 as the first schizophrenia risk genes linked exclusively to missense variants, which alter protein amino acid sequences.
The study identified SLC6A1 and KLC1 as the first schizophrenia risk genes linked exclusively to missense variants, which alter protein amino acid sequences.

Importantly, the study also supports the growing hypothesis that schizophrenia shares genetic roots with other neurodevelopmental disorders. Four of the eight genes identified STAG1, SLC6A1, ZMYND11, and CGREF1 have already been implicated in conditions such as autism, epilepsy, and developmental delay. This overlap reinforces the idea of a shared biological pathway underlying a range of brain-based disorders, suggesting that future research into one condition could provide valuable insights into others. Such cross-disorder genetic associations could pave the way for unified therapeutic strategies targeting common mechanisms.

Dr. Elliot Rees, lead author of the study and researcher at Cardiff University’s School of Medicine, highlighted the significance of these findings in addressing long-standing challenges in psychiatric genetics. “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,” he said. The success of this study in pinpointing both well-supported and suggestive gene associations marks a critical step forward in understanding the genetic foundations of schizophrenia, ultimately moving the field closer to precision medicine approaches in mental health care.

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. Translating these genetic discoveries into treatments is a long-term goal, but the 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 these have only been implicated in 12 genes.

To enhance the statistical power for gene discovery, the researchers analyzed exome sequencing data from a newly collected cohort comprising 4,650 individuals diagnosed with schizophrenia and 5,719 control participants. This dataset was integrated with previously published sequence data, including a total of 28,898 schizophrenia cases, 103,041 controls, and 3,444 proband-parent trios. By aggregating data across such a large and diverse sample, the study was able to detect rare coding variants with higher confidence, offering a more comprehensive understanding of the genetic architecture underlying schizophrenia.

Through this expanded analysis, two genes STAG1 and ZNF136 were identified with exome-wide significance, reinforcing prior findings from the SCHEMA study. These genes met the threshold for significance with a false discovery rate (FDR) of 5%, confirming their strong association with schizophrenia. Additionally, six other genes SLC6A1, PCLO, ZMYND11, BSCL2, KLC1, and CGREF1 were also found to be associated with the disorder at the same FDR threshold, although they had not reached this level of statistical significance in the earlier SCHEMA study. This suggests that the expanded dataset provided the necessary statistical power to validate previously inconclusive signals.

Among these genes, SLC6A1 and KLC1 showed unique associations specifically with deleterious missense mutations, indicating a potential mechanism of dysfunction at the protein level. Notably, STAG1, SLC6A1, ZMYND11, and CGREF1 have also been linked to rare coding variants implicated in other developmental and psychiatric disorders, underscoring shared genetic vulnerabilities across conditions. Furthermore, STAG1 and KLC1 display distinct, well-mapped functional features in the context of schizophrenia, adding to the biological plausibility of their involvement in the disease. These findings contribute valuable insights into the overlapping and unique genetic factors driving schizophrenia and related neurodevelopmental disorders.

These findings provide insights into the neurobiology of schizophrenia, including additional evidence suggesting that altered chromatin organization plays an etiological role.

Conclusion

This large-scale exome sequencing study has significantly advanced our understanding of the genetic underpinnings of schizophrenia. By combining new data with existing global datasets, the research identified rare coding variants in eight genes, including STAG1 and ZNF136, which showed exome-wide significance, and six additional genes that reached statistical relevance at a false discovery rate of 5%. The study not only reinforces previous findings but also uncovers novel associations, particularly in genes such as SLC6A1 and KLC1, which are uniquely linked to deleterious missense mutations. The overlap between schizophrenia-associated genes and those implicated in other neurodevelopmental disorders further highlights a shared genetic architecture, offering new directions for research into early diagnosis, intervention, and cross-disorder treatment strategies. These findings represent a critical step toward precision psychiatry and open new possibilities for understanding and managing schizophrenia through a genetic lens.

Comments

No comments yet. Why don’t you start the discussion?

Leave a Reply

Your email address will not be published. Required fields are marked *