Identification of schizophrenia symptom-related gene modules by postmortem brain transcriptome analysis
Abstract Schizophrenia is a multifactorial disorder, the genetic architecture of which remains unclear. Although many studies have examined the etiology of schizophrenia, the gene sets that contribute to its symptoms have not been fully investigated. In this study, we aimed to identify each gene set...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-05-01
|
| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-023-02449-8 |
| _version_ | 1797831890401492992 |
|---|---|
| author | Kazusa Miyahara Mizuki Hino Risa Shishido Atsuko Nagaoka Ryuta Izumi Hideki Hayashi Akiyoshi Kakita Hirooki Yabe Hiroaki Tomita Yasuto Kunii |
| author_facet | Kazusa Miyahara Mizuki Hino Risa Shishido Atsuko Nagaoka Ryuta Izumi Hideki Hayashi Akiyoshi Kakita Hirooki Yabe Hiroaki Tomita Yasuto Kunii |
| author_sort | Kazusa Miyahara |
| collection | DOAJ |
| description | Abstract Schizophrenia is a multifactorial disorder, the genetic architecture of which remains unclear. Although many studies have examined the etiology of schizophrenia, the gene sets that contribute to its symptoms have not been fully investigated. In this study, we aimed to identify each gene set associated with corresponding symptoms of schizophrenia using the postmortem brains of 26 patients with schizophrenia and 51 controls. We classified genes expressed in the prefrontal cortex (analyzed by RNA-seq) into several modules by weighted gene co-expression network analysis (WGCNA) and examined the correlation between module expression and clinical characteristics. In addition, we calculated the polygenic risk score (PRS) for schizophrenia from Japanese genome-wide association studies, and investigated the association between the identified gene modules and PRS to evaluate whether genetic background affected gene expression. Finally, we conducted pathway analysis and upstream analysis using Ingenuity Pathway Analysis to clarify the functions and upstream regulators of symptom-related gene modules. As a result, three gene modules generated by WGCNA were significantly correlated with clinical characteristics, and one of these showed a significant association with PRS. Genes belonging to the transcriptional module associated with PRS significantly overlapped with signaling pathways of multiple sclerosis, neuroinflammation, and opioid use, suggesting that these pathways may also be profoundly implicated in schizophrenia. Upstream analysis indicated that genes in the detected module were profoundly regulated by lipopolysaccharides and CREB. This study identified schizophrenia symptom-related gene sets and their upstream regulators, revealing aspects of the pathophysiology of schizophrenia and identifying potential therapeutic targets. |
| first_indexed | 2024-04-09T13:58:58Z |
| format | Article |
| id | doaj.art-77eff89cc70b4749b806c704fa3ab4c3 |
| institution | Directory Open Access Journal |
| issn | 2158-3188 |
| language | English |
| last_indexed | 2024-04-09T13:58:58Z |
| publishDate | 2023-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj.art-77eff89cc70b4749b806c704fa3ab4c32023-05-07T11:25:00ZengNature Publishing GroupTranslational Psychiatry2158-31882023-05-0113111010.1038/s41398-023-02449-8Identification of schizophrenia symptom-related gene modules by postmortem brain transcriptome analysisKazusa Miyahara0Mizuki Hino1Risa Shishido2Atsuko Nagaoka3Ryuta Izumi4Hideki Hayashi5Akiyoshi Kakita6Hirooki Yabe7Hiroaki Tomita8Yasuto Kunii9Department of Disaster Psychiatry, International Research Institute of Disaster Science, Tohoku UniversityDepartment of Disaster Psychiatry, International Research Institute of Disaster Science, Tohoku UniversityDepartment of Neuropsychiatry, School of Medicine, Fukushima Medical UniversityDepartment of Neuropsychiatry, School of Medicine, Fukushima Medical UniversityDepartment of Neuropsychiatry, School of Medicine, Fukushima Medical UniversityDepartment of Pathology, Brain Research Institute, Niigata UniversityDepartment of Pathology, Brain Research Institute, Niigata UniversityDepartment of Neuropsychiatry, School of Medicine, Fukushima Medical UniversityDepartment of Psychiatry, Tohoku University HospitalDepartment of Disaster Psychiatry, International Research Institute of Disaster Science, Tohoku UniversityAbstract Schizophrenia is a multifactorial disorder, the genetic architecture of which remains unclear. Although many studies have examined the etiology of schizophrenia, the gene sets that contribute to its symptoms have not been fully investigated. In this study, we aimed to identify each gene set associated with corresponding symptoms of schizophrenia using the postmortem brains of 26 patients with schizophrenia and 51 controls. We classified genes expressed in the prefrontal cortex (analyzed by RNA-seq) into several modules by weighted gene co-expression network analysis (WGCNA) and examined the correlation between module expression and clinical characteristics. In addition, we calculated the polygenic risk score (PRS) for schizophrenia from Japanese genome-wide association studies, and investigated the association between the identified gene modules and PRS to evaluate whether genetic background affected gene expression. Finally, we conducted pathway analysis and upstream analysis using Ingenuity Pathway Analysis to clarify the functions and upstream regulators of symptom-related gene modules. As a result, three gene modules generated by WGCNA were significantly correlated with clinical characteristics, and one of these showed a significant association with PRS. Genes belonging to the transcriptional module associated with PRS significantly overlapped with signaling pathways of multiple sclerosis, neuroinflammation, and opioid use, suggesting that these pathways may also be profoundly implicated in schizophrenia. Upstream analysis indicated that genes in the detected module were profoundly regulated by lipopolysaccharides and CREB. This study identified schizophrenia symptom-related gene sets and their upstream regulators, revealing aspects of the pathophysiology of schizophrenia and identifying potential therapeutic targets.https://doi.org/10.1038/s41398-023-02449-8 |
| spellingShingle | Kazusa Miyahara Mizuki Hino Risa Shishido Atsuko Nagaoka Ryuta Izumi Hideki Hayashi Akiyoshi Kakita Hirooki Yabe Hiroaki Tomita Yasuto Kunii Identification of schizophrenia symptom-related gene modules by postmortem brain transcriptome analysis Translational Psychiatry |
| title | Identification of schizophrenia symptom-related gene modules by postmortem brain transcriptome analysis |
| title_full | Identification of schizophrenia symptom-related gene modules by postmortem brain transcriptome analysis |
| title_fullStr | Identification of schizophrenia symptom-related gene modules by postmortem brain transcriptome analysis |
| title_full_unstemmed | Identification of schizophrenia symptom-related gene modules by postmortem brain transcriptome analysis |
| title_short | Identification of schizophrenia symptom-related gene modules by postmortem brain transcriptome analysis |
| title_sort | identification of schizophrenia symptom related gene modules by postmortem brain transcriptome analysis |
| url | https://doi.org/10.1038/s41398-023-02449-8 |
| work_keys_str_mv | AT kazusamiyahara identificationofschizophreniasymptomrelatedgenemodulesbypostmortembraintranscriptomeanalysis AT mizukihino identificationofschizophreniasymptomrelatedgenemodulesbypostmortembraintranscriptomeanalysis AT risashishido identificationofschizophreniasymptomrelatedgenemodulesbypostmortembraintranscriptomeanalysis AT atsukonagaoka identificationofschizophreniasymptomrelatedgenemodulesbypostmortembraintranscriptomeanalysis AT ryutaizumi identificationofschizophreniasymptomrelatedgenemodulesbypostmortembraintranscriptomeanalysis AT hidekihayashi identificationofschizophreniasymptomrelatedgenemodulesbypostmortembraintranscriptomeanalysis AT akiyoshikakita identificationofschizophreniasymptomrelatedgenemodulesbypostmortembraintranscriptomeanalysis AT hirookiyabe identificationofschizophreniasymptomrelatedgenemodulesbypostmortembraintranscriptomeanalysis AT hiroakitomita identificationofschizophreniasymptomrelatedgenemodulesbypostmortembraintranscriptomeanalysis AT yasutokunii identificationofschizophreniasymptomrelatedgenemodulesbypostmortembraintranscriptomeanalysis |