Whole-exome sequencing analysis identifies risk genes for schizophrenia
- Sophie L. Chick
- Peter Holmans
- Darren Cameron
- Detelina Grozeva
- Rebecca Sims
- Julie Williams
- Nicholas J. Bray
- Michael J. Owen
- Michael C. O’Donovan
- James T. R. Walters
- Elliott Rees
2025-08-02
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.