Whole-exome sequencing analysis identifies risk genes for schizophrenia
Abstract 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 schizoph...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62429-y |
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| author | 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 |
| author_facet | 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 |
| author_sort | Sophie L. Chick |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-60067ad9da244530ac6aaf951cfc76dd |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-60067ad9da244530ac6aaf951cfc76dd2025-08-20T03:05:06ZengNature PortfolioNature Communications2041-17232025-08-011611910.1038/s41467-025-62429-yWhole-exome sequencing analysis identifies risk genes for schizophreniaSophie L. Chick0Peter Holmans1Darren Cameron2Detelina Grozeva3Rebecca Sims4Julie Williams5Nicholas J. Bray6Michael J. Owen7Michael C. O’Donovan8James T. R. Walters9Elliott Rees10Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff UniversityCentre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff UniversityCentre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff UniversityDivision of Psychological Medicine and Clinical Neurosciences, Cardiff UniversityCentre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff UniversityDivision of Psychological Medicine and Clinical Neurosciences, Cardiff UniversityCentre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff UniversityCentre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff UniversityCentre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff UniversityCentre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff UniversityCentre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff UniversityAbstract 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.https://doi.org/10.1038/s41467-025-62429-y |
| spellingShingle | 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 Whole-exome sequencing analysis identifies risk genes for schizophrenia Nature Communications |
| title | Whole-exome sequencing analysis identifies risk genes for schizophrenia |
| title_full | Whole-exome sequencing analysis identifies risk genes for schizophrenia |
| title_fullStr | Whole-exome sequencing analysis identifies risk genes for schizophrenia |
| title_full_unstemmed | Whole-exome sequencing analysis identifies risk genes for schizophrenia |
| title_short | Whole-exome sequencing analysis identifies risk genes for schizophrenia |
| title_sort | whole exome sequencing analysis identifies risk genes for schizophrenia |
| url | https://doi.org/10.1038/s41467-025-62429-y |
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