Genome-wide interaction association analysis identifies interactive effects of childhood maltreatment and kynurenine pathway on depression

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 () and Weihua Yue ()
Additional contact information
Yaoyao Sun: National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)
Yundan Liao: National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)
Yuyanan Zhang: National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)
Zhe Lu: National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)
Yuzhuo Ma: Peking University
Zhewei Kang: National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)
Xiaoyang Feng: National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)
Guorui Zhao: National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)
Junyuan Sun: National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)
Yunqing Zhu: National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)
Rui Yuan: National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)
Yang Yang: National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)
Liangkun Guo: National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)
Xiao Zhang: National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)
Dai Zhang: National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)
Runsen Chen: Tsinghua University
Wenjian Bi: Peking University
Weihua Yue: National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57066-4

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