Summary: The largest exome-sequencing study of schizophrenia to date has uncovered eight new genes tied to the disorder. Two genes, STAG1 and ZNF136, were strongly implicated, while six others showed moderate associations.
Notably, SLC6A1 and KLC1 became the first schizophrenia risk genes linked solely through missense variants, highlighting disruptions in protein function. These findings shed light on genetic mechanisms behind schizophrenia and point toward future diagnostic and therapeutic developments.
Key Facts
- Eight Risk Genes Identified: Two with strong evidence (STAG1, ZNF136) and six with moderate support.
- New Mechanisms: SLC6A1 and KLC1 linked solely through missense variants, altering protein structure.
- Biological Insight: Results suggest schizophrenia may involve DNA organization changes and disrupted GABA signaling.
Source: Cardiff University
Researchers have discovered eight new genes associated with schizophrenia, in the largest exome-sequencing study of the disorder ever conducted.
The breakthrough, made by scientists at the Centre for Neuropsychiatric Genetics and Genomics (CNGG) at Cardiff University, provides new information and improves the understanding and future treatment development for schizophrenia.
The international study, published in Nature Communications, analysed genetic data from 28,898 individuals with schizophrenia, 103,041 without the condition, and 3,444 families affected by the disorder. Researchers focused on detecting rare, high-impact mutations in protein-coding genes that are significantly more common in people with schizophrenia.
The study identified two genes – STAG1 and ZNF136 – that were linked to schizophrenia with strong genetic evidence. An additional six genes – SLC6A1, KLC1, PCLO, ZMYND11, BSCL2, and CGREF – were also associated with more moderate evidence.
The research found that SLC6A1 and KLC1 are the first schizophrenia risk genes to be linked solely through missense variants, a specific type of mutation that alters the amino-acid sequence of proteins.
Sophie Chick, PhD student at Cardiff University, funded by Mental Health Research UK and the Fieldrose Charitable Trust, said: “These findings are informative because they suggest that schizophrenia might be linked to changes in how DNA is organised within cells, and also disruptions in how brain cells communicate using a chemical called GABA.”
The research also strengthens the case for shared genetic roots between schizophrenia and other neurodevelopmental conditions. Four of the newly identified genes – STAG1, SLC6A1, ZMYND11, and CGREF1 – have previously been associated with autism, epilepsy, and developmental delay.
Dr Elliott Rees, from Cardiff University School of Medicine and the study’s lead author, said: “Rare genetic variants have long been known to have a role in schizophrenia, but identifying specific genes linked to these mutations has been a major challenge.”
With only a limited number of risk genes identified before this study, researchers say the findings are a significant leap forward in understanding the complex genetics of schizophrenia.
While translating these genetic discoveries into treatments remains a long-term goal, the results offer new hope for guiding drug development and targeted therapies in the future.
Funding: The research was funded by Medical Research Council, a UKRI Future Leaders Fellowship, and Mental Health Research UK.
About this genetics and schizophrenia research news
Author: Sophie Chick
Source: Cardiff University
Contact: Sophie Chick – Cardiff University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Whole-exome sequencing analysis identifies risk genes for schizophrenia” by Sophie Chick et al. Nature Communications
Abstract
Whole-exome sequencing analysis identifies risk genes for schizophrenia
Rare coding variants across many genes contribute to schizophrenia liability, but they have only been implicated in 12 genes at exome-wide levels of significance.
To increase power for gene discovery, we analyse exome-sequencing data for rare coding variants in a new sample of 4650 schizophrenia cases and 5719 controls, and combine these with published sequencing data for a total of 28,898 cases, 103,041 controls and 3444 proband-parent trios.
We identify associations for STAG1 and ZNF136 at exome-wide significance, genes that were previously implicated in schizophrenia by the SCHEMA study at a false discovery rate of 5%.
We also find associations at a false discovery rate of 5% for six genes that did not pass this statistical threshold in the SCHEMA study (SLC6A1, PCLO, ZMYND11, BSCL2, KLC1 and CGREF1).
Among these genes, SLC6A1 and KLC1 are associated with damaging missense variants alone. STAG1, SLC6A1, ZMYND11 and CGREF1 are also enriched for rare coding variants in other developmental and psychiatric disorders. Moreover, STAG1 and KLC1 have fine-mapped common variant signals in schizophrenia.
These findings provide insights into the neurobiology of schizophrenia, including further evidence suggesting an aetiological role for disrupted chromatin organisation.
