Summary: The largest whole-exome sequencing study to date has identified eight new genes associated with schizophrenia. Two genes, STAG1 and ZNF136, show strong statistical evidence, while six others demonstrate more moderate associations. Notably, SLC6A1 and KLC1 are the first schizophrenia risk genes implicated exclusively through missense variants, pointing to altered protein function as a contributing mechanism.
This international study expands our genetic understanding of schizophrenia and highlights biological pathways that may guide future diagnostics and targeted treatments.
Key facts
- Eight risk genes discovered: Two with exome-wide significance (STAG1, ZNF136) and six with support at a false discovery rate of 5%.
- Missense-variant signal: SLC6A1 and KLC1 were associated solely by damaging missense variants, implicating changes to protein structure or function.
- Biological insights: Findings point to potential roles for chromatin (DNA) organization and disrupted GABAergic signaling in schizophrenia.
Source: Cardiff University
Overview
Researchers at the Centre for Neuropsychiatric Genetics and Genomics (CNGG) at Cardiff University led the largest exome-sequencing investigation of schizophrenia to date. Published in Nature Communications, the study pooled data from many cohorts, analysing genetic information from 28,898 people diagnosed with schizophrenia, 103,041 population controls, and 3,444 family trios. The goal was to find rare, high-impact coding variants in protein-coding genes that occur more frequently in individuals with schizophrenia.
From this large dataset, the team identified two genes—STAG1 and ZNF136—with exome-wide significant associations to schizophrenia. Six additional genes reached statistical support at a false discovery rate of 5%: SLC6A1, KLC1, PCLO, ZMYND11, BSCL2, and CGREF (the report refers to CGREF1 in some sections of the study).
The association of SLC6A1 and KLC1 is noteworthy because these genes were implicated exclusively through damaging missense variants. Missense mutations change a protein’s amino-acid sequence and can disrupt protein structure or function, suggesting a direct impact on molecular processes in the brain.
Sophie Chick, a PhD student at Cardiff University and co-author of the paper, emphasized what these associations reveal about disease biology: “These findings suggest schizophrenia may be linked to changes in how DNA is organised within cells, and to disruptions in how brain cells communicate using the neurotransmitter GABA.” Such insights strengthen the hypothesis that both chromatin organization and synaptic signaling are important to schizophrenia risk.
The study also reinforces the overlap in genetic risk across neurodevelopmental and psychiatric disorders. Four of the genes identified—STAG1, SLC6A1, ZMYND11 and CGREF/CGREF1—have prior connections to conditions such as autism, epilepsy and developmental delay, highlighting shared biological pathways across diagnoses.
Dr Elliott Rees, lead author from Cardiff University School of Medicine, commented that while rare variants have been known to contribute to schizophrenia risk, pinpointing specific genes has been difficult. This study represents a significant step forward by expanding the list of genes confidently linked to the disorder and by clarifying the types of mutations driving risk.
Translating genetic discoveries into new treatments will take time, but identifying genes and the molecular mechanisms they affect creates clearer targets for drug discovery and for developing more precise, biologically informed therapies in the long term.
Funding: The research received funding from the 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 credit: Neuroscience News
Original research: Open access. Title reported in the study: “Whole-exome sequencing analysis identifies risk genes for schizophrenia” by Sophie Chick et al., published in Nature Communications.
Abstract (condensed)
Rare coding variants across many genes contribute to schizophrenia risk, but before this work only a limited set of genes reached exome-wide significance. To boost discovery power, the study combined new exome-sequencing data (4,650 cases and 5,719 controls) with previously published datasets, totaling 28,898 cases, 103,041 controls, and 3,444 proband-parent trios.
The analysis found exome-wide significant associations for STAG1 and ZNF136, and six additional genes at a 5% false discovery rate: SLC6A1, PCLO, ZMYND11, BSCL2, KLC1 and CGREF/CGREF1. Among these, SLC6A1 and KLC1 were associated through damaging missense variants alone. Several identified genes are also enriched for rare variants in other developmental and psychiatric disorders, and some show supporting signals from common-variant studies. Overall, the findings offer new insights into schizophrenia neurobiology, including evidence implicating disrupted chromatin organisation.