TLR4 identified as a major depressive disorder gene signature mediating effects through multiple immune cells
Abstract The pathogenesis of major depressive disorder (MDD) is currently unclear and lacks objective diagnostic criteria. The complexity and heterogeneity of MDD also limit precise treatment. Using bioinformatics methods, we identified 18 gene signatures of MDD from the GSE98793 dataset, and valida...
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Nature Portfolio
2025-04-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-95663-x |
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| author | Jiayi Wei Lei Tang Sijian Wang Xiang Yuan Rong Liao Yuling Wu NanQi Huang Hangchi Liu Hanyan Wang |
| author_facet | Jiayi Wei Lei Tang Sijian Wang Xiang Yuan Rong Liao Yuling Wu NanQi Huang Hangchi Liu Hanyan Wang |
| author_sort | Jiayi Wei |
| collection | DOAJ |
| description | Abstract The pathogenesis of major depressive disorder (MDD) is currently unclear and lacks objective diagnostic criteria. The complexity and heterogeneity of MDD also limit precise treatment. Using bioinformatics methods, we identified 18 gene signatures of MDD from the GSE98793 dataset, and validated them in an independent dataset GSE44593 (Area under the curve values were 0.92, 0.72, and 0.70 for the training, validation, and test sets, respectively). Among the gene signatures, TLR4 had the largest absolute coefficient value (coefficient = -6.13). We further identified three CD 14 + monocyte-associated gene signatures and two immune-related subtypes. The expression of TLR4 is significantly increased in subtype A of MDD (lower predicted probability), and is significantly correlated with the composition of multiple immune cells (P < 0.05). We validated that TLR4 acts as a protective factor in MDD (OR = 0.91, 95% CI = 0.85 to 0.98, P = 0.012), and its expression is driven by the same causal variants as MDD (H4/(H3 + H4) = 98.62%). Further analysis showed that the relationship between TLR4 and MDD is influenced by eight immune cell signatures. Our research provided genetic support that the immune factors may play an important role in MDD, and proposed a possible strategy for the diagnosis and treatment of MDD. |
| format | Article |
| id | doaj-art-7c477691a5c84f60b0d68e9947064d8a |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-7c477691a5c84f60b0d68e9947064d8a2025-08-20T02:12:06ZengNature PortfolioScientific Reports2045-23222025-04-0115111410.1038/s41598-025-95663-xTLR4 identified as a major depressive disorder gene signature mediating effects through multiple immune cellsJiayi Wei0Lei Tang1Sijian Wang2Xiang Yuan3Rong Liao4Yuling Wu5NanQi Huang6Hangchi Liu7Hanyan Wang8Institute of Basic Medicine, North Sichuan Medical CollegeMental Health Center, Affiliated Hospital of North Sichuan Medical CollegeDepartment of Clinical Medicine, North Sichuan Medical CollegeNanchong Psychosomatic HospitalNanchong Psychosomatic HospitalNanchong Psychosomatic HospitalDepartment of Clinical Medicine, North Sichuan Medical CollegeDepartment of Clinical Medicine, North Sichuan Medical CollegeInstitute of Basic Medicine, North Sichuan Medical CollegeAbstract The pathogenesis of major depressive disorder (MDD) is currently unclear and lacks objective diagnostic criteria. The complexity and heterogeneity of MDD also limit precise treatment. Using bioinformatics methods, we identified 18 gene signatures of MDD from the GSE98793 dataset, and validated them in an independent dataset GSE44593 (Area under the curve values were 0.92, 0.72, and 0.70 for the training, validation, and test sets, respectively). Among the gene signatures, TLR4 had the largest absolute coefficient value (coefficient = -6.13). We further identified three CD 14 + monocyte-associated gene signatures and two immune-related subtypes. The expression of TLR4 is significantly increased in subtype A of MDD (lower predicted probability), and is significantly correlated with the composition of multiple immune cells (P < 0.05). We validated that TLR4 acts as a protective factor in MDD (OR = 0.91, 95% CI = 0.85 to 0.98, P = 0.012), and its expression is driven by the same causal variants as MDD (H4/(H3 + H4) = 98.62%). Further analysis showed that the relationship between TLR4 and MDD is influenced by eight immune cell signatures. Our research provided genetic support that the immune factors may play an important role in MDD, and proposed a possible strategy for the diagnosis and treatment of MDD.https://doi.org/10.1038/s41598-025-95663-xMajor depressive disorderGene signatureImmune signatureTLR4Mendelian randomization |
| spellingShingle | Jiayi Wei Lei Tang Sijian Wang Xiang Yuan Rong Liao Yuling Wu NanQi Huang Hangchi Liu Hanyan Wang TLR4 identified as a major depressive disorder gene signature mediating effects through multiple immune cells Scientific Reports Major depressive disorder Gene signature Immune signature TLR4 Mendelian randomization |
| title | TLR4 identified as a major depressive disorder gene signature mediating effects through multiple immune cells |
| title_full | TLR4 identified as a major depressive disorder gene signature mediating effects through multiple immune cells |
| title_fullStr | TLR4 identified as a major depressive disorder gene signature mediating effects through multiple immune cells |
| title_full_unstemmed | TLR4 identified as a major depressive disorder gene signature mediating effects through multiple immune cells |
| title_short | TLR4 identified as a major depressive disorder gene signature mediating effects through multiple immune cells |
| title_sort | tlr4 identified as a major depressive disorder gene signature mediating effects through multiple immune cells |
| topic | Major depressive disorder Gene signature Immune signature TLR4 Mendelian randomization |
| url | https://doi.org/10.1038/s41598-025-95663-x |
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