Abstract
Schizophrenia (SCZ) and depression are two prevalent mental disorders characterized by comorbidity and overlapping symptoms, yet the underlying genetic and neural mechanisms remain largely elusive. Here, we investigated the genetic variants and neuroimaging changes shared by SCZ and depression in Europeans and then extended our investigation to cross-ancestry (Europeans and East Asians) populations. Using conditional and conjunctional analyses, we found 213 genetic variants shared by SCZ and depression in Europeans, of which 82.6% were replicated in the cross-ancestry population. The shared risk variants exhibited a higher degree of deleteriousness than random and were enriched for synapse-related functions, among which fewer than 3% of shared variants showed horizontal pleiotropy between the two disorders. Mendelian randomization analyses indicated reciprocal causal effects between SCZ and depression. Using multiple trait genetic colocalization analyses, we pinpointed 13 volume phenotypes shared by SCZ and depression. Particularly noteworthy were the shared volume reductions in the left insula and planum polare, which were validated through large-scale meta-analyses of previous studies and independent neuroimaging datasets of first-episode drug-naïve patients. These findings suggest that the shared genetic risk variants, synapse dysfunction, and brain structural changes may underlie the comorbidity and symptom overlap between SCZ and depression.
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Fig. 1: The study design.
Fig. 2: Shared genetic risk variants between SCZ and depression.
Fig. 3: Pleiotropic mechanisms of shared SNPs and bidirectional causal effects between SCZ and depression.
Fig. 4: Functional annotations of genetic risk SNPs shared by SCZ and depression.
Fig. 5: Shared GMV phenotypes between SCZ and depression.
Data availability
The GWAS summary statistics for both SCZ and depression are publicly available at the Psychiatric Genomics Consortium (https://www.med.unc.edu/pgc/). The EUR-GWAS summary statistics for GMV phenotypes in 33,224 UKBB participants are available on UKBB website (https://open.win.ox.ac.uk/ukbiobank/big40/). The cross-ancestry GWAS summary statistics for GMV phenotypes in 7,058 CHIMGEN and 33,224 UKBB participants are available on the website (http://www.mulinlab.org/pheweb/). Individual-level neuroimaging data supporting the findings of this study are not openly available. However, we encourage researchers interested in collaboration for non-commercial use to email CY (chunshuiyu@tmu.edu.cn). All data requests will be reviewed to verify whether the request is subject to any intellectual property or confidentiality obligations.
Code availability
All the software and code used in this study are publicly available and are described in the Methods.
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Acknowledgements
We thank all participants and researchers of the CHIMGEN study, who generously donated their time to make this resource available. We are grateful to all patients and healthy controls from Tianjin Medical University General Hospital and First Psychiatric Hospital of Harbin. We thank the Psychiatric Genomics Consortium (PGC) group for providing GWAS summary statistics of SCZ and depression. We acknowledge UK Biobank for providing GWAS summary statistics for brain imaging phenotypes. We acknowledge funding from the National Natural Science Foundation of China (82430063, 82030053, 81425013, 82402253, 82072001), the National Key Research and Development Program of China (2018YFC1314300), the Beijing-Tianjin-Hebei Basic Research Collaboration Project (J230040), the Tianjin Natural Science Foundation (23JCZXJC00120) and the Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-001A). Figure 1 was partly generated using Servier Medical Art (https://smart.servier.com/), licensed under a Creative Commons Attribution 4.0 Unported License.
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These authors contributed equally: Yingying Xie, Jilian Fu.
Authors and Affiliations
Department of Radiology & Tianjin Key Lab of Functional Imaging & Tianjin Institute of Radiology & State Key Laboratory of Experimental Hematology, Tianjin Medical University General Hospital, Tianjin, 300052, China
Yingying Xie, Jilian Fu, Feng Liu, Wen Qin & Chunshui Yu
The First Psychiatric Hospital of Harbin, Harbin, 150056, China
Liping Liu & Xijin Wang
School of Medical Imaging, Tianjin Medical University, Tianjin, 300203, China
Meng Liang & Chunshui Yu
Division of Brain Sciences, Changping Laboratory, Beijing, 102206, China
Hesheng Liu
Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, 100871, China
Hesheng Liu
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Yingying Xie
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Contributions
CY and YX designed the study. YX and JF analyzed the data. YX, JF, HL, WQ, and CY wrote the manuscript. CY and WQ supervised this work. YX, JF, LL, XW, FL, and ML acquired the data. All authors critically reviewed the manuscript.
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Correspondence to Hesheng Liu, Wen Qin or Chunshui Yu.
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All methods were performed in accordance with the relevant guidelines and regulations. Ethical approval for publicly available GWAS summary statistics was obtained from the respective ethics committees or institutional review boards, with informed consent obtained from participants in the original studies. For individual-level neuroimaging data, approval was granted by the Medical Ethical Committee of Tianjin Medical University General Hospital (IRB2018-179-01) and the First Psychiatric Hospital of Harbin (IRB2018-001), with informed consent obtained from all participants.
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Xie, Y., Fu, J., Liu, L. et al. Genetic and neural mechanisms shared by schizophrenia and depression. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-02975-5
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Received:31 July 2024
Revised:04 March 2025
Accepted:21 March 2025
Published:03 April 2025
DOI:https://doi.org/10.1038/s41380-025-02975-5
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