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Peer-reviewedCC BY-NC-ND 4.0Schizophrenia

Shared genetic architecture between schizophrenia and subcortical brain susceptibility phenotypes

  • Yingying Xie1,2
  • Jiaojiao Du3
  • Yao Zhao4
  • Jie Sun5
  • Shiqi Lin1,2
  • Ningnannan Zhang5
  • Zhang Zhang5
  • Feng Liu5
  • Dairong Cao1,2,6,7
7 affiliations
  1. 1Department of Radiology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
  2. 2Department of Radiology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
  3. 3Department of Breast Imaging, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
  4. 4Department of Radiology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
  5. 5Department of Radiology, Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin, China
  6. 6Fujian Key Laboratory of Precision Medicine for Cancer, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
  7. 7Key Laboratory of Radiation Biology of Fujian Higher Education Institutions, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
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Abstract

Schizophrenia (SCZ) is a highly heritable and complex neuropsychiatric disorder. Emerging evidence implicates dysregulated brain iron, particularly in subcortical regions, in SCZ pathophysiology. Here, we systematically dissected the shared genetic architecture between SCZ and subcortical brain susceptibility phenotypes by integrating large-scale genome-wide association study (GWAS) data with quantitative susceptibility mapping (QSM) phenotypes across 16 subcortical regions. Using the MiXeR framework, we quantified the extent and pattern of shared genetic overlap between SCZ and each QSM phenotype, revealing the strongest overlap in the left and right nucleus accumbens. Conditional and conjunction false discovery rate analyses identified 666 unique shared SNPs. Functional annotation highlighted enrichment in pathways related to synaptic function and neuronal development, with pronounced expression in neurons. Additionally, we characterized their spatio-temporal expression patterns of shared genes and identified 89 significant expression-trait associations linked to SCZ-related phenotypes. Furthermore, the virtual drug screen identified 691 potential protein-drug pairs that may contribute to both iron regulation and SCZ. Our findings provide new insights into the complex interaction between subcortical brain susceptibility phenotypes and SCZ, highlighting pathways that may offer novel therapeutic strategies for SCZ and related brain susceptibility-associated conditions.

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Cite

BibTeXRIS
BibTeX
@article{xie2026shared,
  title = {{Shared genetic architecture between schizophrenia and subcortical brain susceptibility phenotypes}},
  author = {Yingying Xie and Jiaojiao Du and Yao Zhao and Jie Sun and Shiqi Lin and Ningnannan Zhang and Zhang Zhang and Feng Liu and Dairong Cao},
  journal = {Schizophrenia},
  year = {2026},
  month = jul,
  doi = {10.1038/s41537-026-00782-7},
  url = {https://doi.org/10.1038/s41537-026-00782-7},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Shared genetic architecture between schizophrenia and subcortical brain susceptibility phenotypes
AU  - Yingying Xie
AU  - Jiaojiao Du
AU  - Yao Zhao
AU  - Jie Sun
AU  - Shiqi Lin
AU  - Ningnannan Zhang
AU  - Zhang Zhang
AU  - Feng Liu
AU  - Dairong Cao
PY  - 2026
DA  - 2026/07/07
JO  - Schizophrenia
DO  - 10.1038/s41537-026-00782-7
UR  - https://doi.org/10.1038/s41537-026-00782-7
AB  - Schizophrenia (SCZ) is a highly heritable and complex neuropsychiatric disorder. Emerging evidence implicates dysregulated brain iron, particularly in subcortical regions, in SCZ pathophysiology. Here, we systematically dissected the shared genetic architecture between SCZ and subcortical brain susceptibility phenotypes by integrating large-scale genome-wide association study (GWAS) data with quantitative susceptibility mapping (QSM) phenotypes across 16 subcortical regions. Using the MiXeR framework, we quantified the extent and pattern of shared genetic overlap between SCZ and each QSM phenotype, revealing the strongest overlap in the left and right nucleus accumbens. Conditional and conjunction false discovery rate analyses identified 666 unique shared SNPs. Functional annotation highlighted enrichment in pathways related to synaptic function and neuronal development, with pronounced expression in neurons. Additionally, we characterized their spatio-temporal expression patterns of shared genes and identified 89 significant expression-trait associations linked to SCZ-related phenotypes. Furthermore, the virtual drug screen identified 691 potential protein-drug pairs that may contribute to both iron regulation and SCZ. Our findings provide new insights into the complex interaction between subcortical brain susceptibility phenotypes and SCZ, highlighting pathways that may offer novel therapeutic strategies for SCZ and related brain susceptibility-associated conditions.
SN  - 2754-6993
ER  -