Genome-wide interaction association analysis identifies interactive effects of childhood maltreatment and kynurenine pathway on depression
Abstract Childhood maltreatment stands out as a pivotal risk factor for depression, with gene-by-environment interaction serving as a crucial mechanism. Here we perform genome-wide interaction analyzes of childhood maltreatment in the UK Biobank, integrating methylation evidence through colocalizati...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57066-4 |
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| author | Yaoyao Sun Yundan Liao Yuyanan Zhang Zhe Lu Yuzhuo Ma Zhewei Kang Xiaoyang Feng Guorui Zhao Junyuan Sun Yunqing Zhu Rui Yuan Yang Yang Liangkun Guo Xiao Zhang Dai Zhang Runsen Chen Wenjian Bi Weihua Yue |
| author_facet | Yaoyao Sun Yundan Liao Yuyanan Zhang Zhe Lu Yuzhuo Ma Zhewei Kang Xiaoyang Feng Guorui Zhao Junyuan Sun Yunqing Zhu Rui Yuan Yang Yang Liangkun Guo Xiao Zhang Dai Zhang Runsen Chen Wenjian Bi Weihua Yue |
| author_sort | Yaoyao Sun |
| collection | DOAJ |
| description | Abstract Childhood maltreatment stands out as a pivotal risk factor for depression, with gene-by-environment interaction serving as a crucial mechanism. Here we perform genome-wide interaction analyzes of childhood maltreatment in the UK Biobank, integrating methylation evidence through colocalization analysis and identifying associated brain structure abnormalities from childhood to adulthood. A genome-wide significant genomic region interacting with childhood maltreatment is identified at 8p11.21 (IDO2 rs7846217, P = 2.02e–08), implicating the tryptophan-kynurenine pathway. Colocalization analysis reveals that IDO2 rs11777027, rs2340953 and rs28631334 are associated with depression in individuals exposed to childhood maltreatment and colocalize with methylation signals in both blood and brain for IDO2. These interactions affect cortical thickness of the left supramarginal gyrus in children (P = 9.72e–04) and adults (P = 1.34e–04), as well as cortical volume in the right angular gyrus in children (P = 1.02e–04). Furthermore, the interactions significantly predict new-onset depression at a 2-year follow-up in children. Stunted increase in cortical thickness of the left middle-anterior cingulate gyrus and sulcus significantly mediates the interaction between childhood maltreatment and IDO2 on childhood depression. These interactions also moderate antidepressant treatment efficacy at 4–6 weeks. |
| format | Article |
| id | doaj-art-4f27f79d562a458b94b8df2511dd9675 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-4f27f79d562a458b94b8df2511dd96752025-08-20T03:10:52ZengNature PortfolioNature Communications2041-17232025-02-0116111210.1038/s41467-025-57066-4Genome-wide interaction association analysis identifies interactive effects of childhood maltreatment and kynurenine pathway on depressionYaoyao Sun0Yundan Liao1Yuyanan Zhang2Zhe Lu3Yuzhuo Ma4Zhewei Kang5Xiaoyang Feng6Guorui Zhao7Junyuan Sun8Yunqing Zhu9Rui Yuan10Yang Yang11Liangkun Guo12Xiao Zhang13Dai Zhang14Runsen Chen15Wenjian Bi16Weihua Yue17Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)Department of Medical Genetics, School of Basic Medical Sciences, Peking UniversityPeking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)Vanke School of Public Health, Tsinghua UniversityDepartment of Medical Genetics, School of Basic Medical Sciences, Peking UniversityPeking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)Abstract Childhood maltreatment stands out as a pivotal risk factor for depression, with gene-by-environment interaction serving as a crucial mechanism. Here we perform genome-wide interaction analyzes of childhood maltreatment in the UK Biobank, integrating methylation evidence through colocalization analysis and identifying associated brain structure abnormalities from childhood to adulthood. A genome-wide significant genomic region interacting with childhood maltreatment is identified at 8p11.21 (IDO2 rs7846217, P = 2.02e–08), implicating the tryptophan-kynurenine pathway. Colocalization analysis reveals that IDO2 rs11777027, rs2340953 and rs28631334 are associated with depression in individuals exposed to childhood maltreatment and colocalize with methylation signals in both blood and brain for IDO2. These interactions affect cortical thickness of the left supramarginal gyrus in children (P = 9.72e–04) and adults (P = 1.34e–04), as well as cortical volume in the right angular gyrus in children (P = 1.02e–04). Furthermore, the interactions significantly predict new-onset depression at a 2-year follow-up in children. Stunted increase in cortical thickness of the left middle-anterior cingulate gyrus and sulcus significantly mediates the interaction between childhood maltreatment and IDO2 on childhood depression. These interactions also moderate antidepressant treatment efficacy at 4–6 weeks.https://doi.org/10.1038/s41467-025-57066-4 |
| spellingShingle | Yaoyao Sun Yundan Liao Yuyanan Zhang Zhe Lu Yuzhuo Ma Zhewei Kang Xiaoyang Feng Guorui Zhao Junyuan Sun Yunqing Zhu Rui Yuan Yang Yang Liangkun Guo Xiao Zhang Dai Zhang Runsen Chen Wenjian Bi Weihua Yue Genome-wide interaction association analysis identifies interactive effects of childhood maltreatment and kynurenine pathway on depression Nature Communications |
| title | Genome-wide interaction association analysis identifies interactive effects of childhood maltreatment and kynurenine pathway on depression |
| title_full | Genome-wide interaction association analysis identifies interactive effects of childhood maltreatment and kynurenine pathway on depression |
| title_fullStr | Genome-wide interaction association analysis identifies interactive effects of childhood maltreatment and kynurenine pathway on depression |
| title_full_unstemmed | Genome-wide interaction association analysis identifies interactive effects of childhood maltreatment and kynurenine pathway on depression |
| title_short | Genome-wide interaction association analysis identifies interactive effects of childhood maltreatment and kynurenine pathway on depression |
| title_sort | genome wide interaction association analysis identifies interactive effects of childhood maltreatment and kynurenine pathway on depression |
| url | https://doi.org/10.1038/s41467-025-57066-4 |
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