Exon-variant interplay and multi-modal evidence identify endocrine dysregulation in severe psychiatric disorders impacting excitatory neurons
Abstract Bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia share genetic architecture, yet their molecular mechanisms remain elusive. Both common and rare genetic variants contribute to neural dysfunction, impacting cognition and behavior. This study investigates the molecula...
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Nature Publishing Group
2025-04-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-025-03366-8 |
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| author | Karolina Worf Natalie Matosin Nathalie Gerstner Anna S. Fröhlich Anna C. Koller Franziska Degenhardt Holger Thiele Marcella Rietschel Madhara Udawela Elizabeth Scarr Brian Dean Fabian J. Theis Nikola S. Mueller Janine Knauer-Arloth |
| author_facet | Karolina Worf Natalie Matosin Nathalie Gerstner Anna S. Fröhlich Anna C. Koller Franziska Degenhardt Holger Thiele Marcella Rietschel Madhara Udawela Elizabeth Scarr Brian Dean Fabian J. Theis Nikola S. Mueller Janine Knauer-Arloth |
| author_sort | Karolina Worf |
| collection | DOAJ |
| description | Abstract Bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia share genetic architecture, yet their molecular mechanisms remain elusive. Both common and rare genetic variants contribute to neural dysfunction, impacting cognition and behavior. This study investigates the molecular effects of genetic variants on human cortical single-cell types using a single-exon analysis approach. Integrating exon-level eQTLs (common variants influencing exon expression) and joint exon eQT-Scores (combining polygenic risk scores with exon-level gene expression) from a postmortem psychiatric cohort (BD = 15, MDD = 24, schizophrenia = 68, controls = 62) with schizophrenia-focused rare variant data from the SCHEMA consortium, we identified 110 core genes enriched in pathways including circadian entrainment (FDR = 0.02), cortisol synthesis and secretion (FDR = 0.026), and dopaminergic synapse (FDR = 0.038). Additional enriched pathways included hormone signaling (FDRs < 0.0298, including insulin, GnRH, aldosterone, and growth hormone pathways) and, notably, adrenergic signaling in cardiomyocytes (FDR = 0.0028). These pathways highlight shared molecular mechanisms in the three disorders. Single-nuclei RNA sequencing data from three cortical regions revealed that these core set genes are predominantly expressed in excitatory neuron layers 2–6 of the dorsolateral prefrontal cortex, linking molecular changes to cell types involved in cognitive dysfunction. Our results demonstrate the power of integrating multimodal genetic and transcriptomic data at the exon level. This approach moves beyond symptom-based diagnoses toward molecular classifications, identifying potential therapeutic targets for psychiatric disorders. |
| format | Article |
| id | doaj-art-ebb5fe6cab2d4d8a9c9000a8d8339fc3 |
| institution | DOAJ |
| issn | 2158-3188 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj-art-ebb5fe6cab2d4d8a9c9000a8d8339fc32025-08-20T03:18:31ZengNature Publishing GroupTranslational Psychiatry2158-31882025-04-0115111310.1038/s41398-025-03366-8Exon-variant interplay and multi-modal evidence identify endocrine dysregulation in severe psychiatric disorders impacting excitatory neuronsKarolina Worf0Natalie Matosin1Nathalie Gerstner2Anna S. Fröhlich3Anna C. Koller4Franziska Degenhardt5Holger Thiele6Marcella Rietschel7Madhara Udawela8Elizabeth Scarr9Brian Dean10Fabian J. Theis11Nikola S. Mueller12Janine Knauer-Arloth13Institute of Computational Biology, Helmholtz CenterDepartment of Gene and Environment, Max Planck Institute of PsychiatryInstitute of Computational Biology, Helmholtz CenterDepartment of Gene and Environment, Max Planck Institute of PsychiatryInstitute of Human Genetics, University of BonnInstitute of Human Genetics, University of BonnCologne Center for Genomics, University of CologneDepartment of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University Medical Center Mannheim/University of HeidelbergThe Molecular Psychiatry Laboratory, The Florey Institute of Neuroscience and Mental HealthThe Department of Psychiatry, The University of MelbourneThe Molecular Psychiatry Laboratory, The Florey Institute of Neuroscience and Mental HealthInstitute of Computational Biology, Helmholtz CenterInstitute of Computational Biology, Helmholtz CenterInstitute of Computational Biology, Helmholtz CenterAbstract Bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia share genetic architecture, yet their molecular mechanisms remain elusive. Both common and rare genetic variants contribute to neural dysfunction, impacting cognition and behavior. This study investigates the molecular effects of genetic variants on human cortical single-cell types using a single-exon analysis approach. Integrating exon-level eQTLs (common variants influencing exon expression) and joint exon eQT-Scores (combining polygenic risk scores with exon-level gene expression) from a postmortem psychiatric cohort (BD = 15, MDD = 24, schizophrenia = 68, controls = 62) with schizophrenia-focused rare variant data from the SCHEMA consortium, we identified 110 core genes enriched in pathways including circadian entrainment (FDR = 0.02), cortisol synthesis and secretion (FDR = 0.026), and dopaminergic synapse (FDR = 0.038). Additional enriched pathways included hormone signaling (FDRs < 0.0298, including insulin, GnRH, aldosterone, and growth hormone pathways) and, notably, adrenergic signaling in cardiomyocytes (FDR = 0.0028). These pathways highlight shared molecular mechanisms in the three disorders. Single-nuclei RNA sequencing data from three cortical regions revealed that these core set genes are predominantly expressed in excitatory neuron layers 2–6 of the dorsolateral prefrontal cortex, linking molecular changes to cell types involved in cognitive dysfunction. Our results demonstrate the power of integrating multimodal genetic and transcriptomic data at the exon level. This approach moves beyond symptom-based diagnoses toward molecular classifications, identifying potential therapeutic targets for psychiatric disorders.https://doi.org/10.1038/s41398-025-03366-8 |
| spellingShingle | Karolina Worf Natalie Matosin Nathalie Gerstner Anna S. Fröhlich Anna C. Koller Franziska Degenhardt Holger Thiele Marcella Rietschel Madhara Udawela Elizabeth Scarr Brian Dean Fabian J. Theis Nikola S. Mueller Janine Knauer-Arloth Exon-variant interplay and multi-modal evidence identify endocrine dysregulation in severe psychiatric disorders impacting excitatory neurons Translational Psychiatry |
| title | Exon-variant interplay and multi-modal evidence identify endocrine dysregulation in severe psychiatric disorders impacting excitatory neurons |
| title_full | Exon-variant interplay and multi-modal evidence identify endocrine dysregulation in severe psychiatric disorders impacting excitatory neurons |
| title_fullStr | Exon-variant interplay and multi-modal evidence identify endocrine dysregulation in severe psychiatric disorders impacting excitatory neurons |
| title_full_unstemmed | Exon-variant interplay and multi-modal evidence identify endocrine dysregulation in severe psychiatric disorders impacting excitatory neurons |
| title_short | Exon-variant interplay and multi-modal evidence identify endocrine dysregulation in severe psychiatric disorders impacting excitatory neurons |
| title_sort | exon variant interplay and multi modal evidence identify endocrine dysregulation in severe psychiatric disorders impacting excitatory neurons |
| url | https://doi.org/10.1038/s41398-025-03366-8 |
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