| Title: | Genome-wide interaction association analysis identifies interactive effects of childhood maltreatment and kynurenine pathway on depression |
| Journal: | Nature Communications |
| Published: | 18 Feb 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39966400/ |
| DOI: | https://doi.org/10.1038/s41467-025-57066-4 |
Publication 14381
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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.</p>
17 Keywords
- Adult
- Brain
- Child
- Child Abuse
- DNA Methylation
- Depression
- Female
- Gene-Environment Interaction
- Genome-Wide Association Study
- Humans
- Indoleamine-Pyrrole 2,3,-Dioxygenase
- Kynurenine
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Tryptophan
- United Kingdom
18 Authors
- 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
1 Application
| Application ID | Title |
|---|---|
| 78795 | Regression methods for phenome-wide association analysis on large-scale biobank data |
Enabling scientific discoveries that improve human health