Large-scale transcriptomic analyses of major depressive disorder reveal convergent dysregulation of synaptic pathways in excitatory neurons
Abstract Major Depressive Disorder (MDD) is a common, complex disorder that is a leading cause of disability worldwide and a significant risk factor for suicide. In this study, we have performed the largest molecular analysis of MDD in postmortem human brains (846 samples across 458 individuals) in...
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59115-4 |
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| author | Fernando S. Goes Leonardo Collado-Torres Peter P. Zandi Louise Huuki-Myers Ran Tao Andrew E. Jaffe Geo Pertea Joo Heon Shin Daniel R. Weinberger Joel E. Kleinman Thomas M. Hyde |
| author_facet | Fernando S. Goes Leonardo Collado-Torres Peter P. Zandi Louise Huuki-Myers Ran Tao Andrew E. Jaffe Geo Pertea Joo Heon Shin Daniel R. Weinberger Joel E. Kleinman Thomas M. Hyde |
| author_sort | Fernando S. Goes |
| collection | DOAJ |
| description | Abstract Major Depressive Disorder (MDD) is a common, complex disorder that is a leading cause of disability worldwide and a significant risk factor for suicide. In this study, we have performed the largest molecular analysis of MDD in postmortem human brains (846 samples across 458 individuals) in the subgenual Anterior Cingulate Cortex (sACC) and the Amygdala, two regions central to mood regulation and the pathophysiology of MDD. We found extensive expression differences, particularly at the level of specific transcripts, with prominent enrichment for genes associated with the vesicular functioning, the postsynaptic density, GTPase signaling, and gene splicing. We find associated transcriptional features in 107 of 243 genome-wide significant loci for MDD and, through integrative analyses, highlight convergence of genetic risk, gene expression, and network-based analyses on dysregulated glutamatergic signaling and synaptic vesicular functioning. Together, these results provide an initial mechanistic understanding of MDD and highlight potential targets for novel drug discovery. |
| format | Article |
| id | doaj-art-7a109b01708c4c079a51cffda66a7cd3 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-7a109b01708c4c079a51cffda66a7cd32025-08-20T02:10:53ZengNature PortfolioNature Communications2041-17232025-04-0116111510.1038/s41467-025-59115-4Large-scale transcriptomic analyses of major depressive disorder reveal convergent dysregulation of synaptic pathways in excitatory neuronsFernando S. Goes0Leonardo Collado-Torres1Peter P. Zandi2Louise Huuki-Myers3Ran Tao4Andrew E. Jaffe5Geo Pertea6Joo Heon Shin7Daniel R. Weinberger8Joel E. Kleinman9Thomas M. Hyde10Department of Psychiatry and Behavioral Sciences, Stanley and Elizabeth Star Precision Medicine Center of Excellence in Mood Disorders, Johns Hopkins School of MedicineThe Lieber Institute for Brain DevelopmentDepartment of Psychiatry and Behavioral Sciences, Stanley and Elizabeth Star Precision Medicine Center of Excellence in Mood Disorders, Johns Hopkins School of MedicineThe Lieber Institute for Brain DevelopmentThe Lieber Institute for Brain DevelopmentThe Lieber Institute for Brain DevelopmentThe Lieber Institute for Brain DevelopmentThe Lieber Institute for Brain DevelopmentThe Lieber Institute for Brain DevelopmentDepartment of Psychiatry and Behavioral Sciences, Stanley and Elizabeth Star Precision Medicine Center of Excellence in Mood Disorders, Johns Hopkins School of MedicineThe Lieber Institute for Brain DevelopmentAbstract Major Depressive Disorder (MDD) is a common, complex disorder that is a leading cause of disability worldwide and a significant risk factor for suicide. In this study, we have performed the largest molecular analysis of MDD in postmortem human brains (846 samples across 458 individuals) in the subgenual Anterior Cingulate Cortex (sACC) and the Amygdala, two regions central to mood regulation and the pathophysiology of MDD. We found extensive expression differences, particularly at the level of specific transcripts, with prominent enrichment for genes associated with the vesicular functioning, the postsynaptic density, GTPase signaling, and gene splicing. We find associated transcriptional features in 107 of 243 genome-wide significant loci for MDD and, through integrative analyses, highlight convergence of genetic risk, gene expression, and network-based analyses on dysregulated glutamatergic signaling and synaptic vesicular functioning. Together, these results provide an initial mechanistic understanding of MDD and highlight potential targets for novel drug discovery.https://doi.org/10.1038/s41467-025-59115-4 |
| spellingShingle | Fernando S. Goes Leonardo Collado-Torres Peter P. Zandi Louise Huuki-Myers Ran Tao Andrew E. Jaffe Geo Pertea Joo Heon Shin Daniel R. Weinberger Joel E. Kleinman Thomas M. Hyde Large-scale transcriptomic analyses of major depressive disorder reveal convergent dysregulation of synaptic pathways in excitatory neurons Nature Communications |
| title | Large-scale transcriptomic analyses of major depressive disorder reveal convergent dysregulation of synaptic pathways in excitatory neurons |
| title_full | Large-scale transcriptomic analyses of major depressive disorder reveal convergent dysregulation of synaptic pathways in excitatory neurons |
| title_fullStr | Large-scale transcriptomic analyses of major depressive disorder reveal convergent dysregulation of synaptic pathways in excitatory neurons |
| title_full_unstemmed | Large-scale transcriptomic analyses of major depressive disorder reveal convergent dysregulation of synaptic pathways in excitatory neurons |
| title_short | Large-scale transcriptomic analyses of major depressive disorder reveal convergent dysregulation of synaptic pathways in excitatory neurons |
| title_sort | large scale transcriptomic analyses of major depressive disorder reveal convergent dysregulation of synaptic pathways in excitatory neurons |
| url | https://doi.org/10.1038/s41467-025-59115-4 |
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