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Powering the mind: deciphering the shared genetic architecture between mitochondrial DNA copy number and major psychiatric disorders

Molecular Psychiatry (2026)Cite this article

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Abstract

Mitochondrial DNA copy number (mtDNA-CN) reflects mitochondrial function and has been associated with several psychiatric disorders. However, the shared genetic architecture between mtDNA-CN and psychiatric conditions remains largely unexplored. Utilizing the largest available genome-wide association study (GWAS) summary statistics from individuals of European ancestry, we systematically investigated the shared genetic architecture between mtDNA-CN and five major psychiatric disorders, including attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). Specifically, we assessed genetic overlap at the global, regional, and variant levels. In addition, gene expression analyses were performed to identify genes whose predicted expression was associated with both mtDNA-CN and psychiatric traits. Functional enrichment analyses were conducted to characterize the biological functions underlying the shared genes. Significant global-level genetic overlap was observed between mtDNA-CN and all five psychiatric disorders. Regional analyses identified four genomic regions with high pleiotropic probability shared between mtDNA-CN and ADHD, BD, and SCZ. At the variant level, 30 lead variants were detected, corresponding to 30 independent loci jointly associated with mtDNA-CN and psychiatric traits. These loci were mapped to 305 unique genes, among which 87 genes exhibited significant associations between their predicted expression levels and both mtDNA-CN and psychiatric disorders. Functional enrichment highlighted neurodevelopmental and ubiquitin-related pathways, with significant downregulation of shared genes in key brain regions. These findings provide comprehensive evidence for shared genetic mechanisms linking mitochondrial function and psychiatric disorders, highlighting mitochondrial dysfunction as a promising target for future therapy.

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Fig. 1: Overview of the analytic framework.
Fig. 2: Results of genetic overlap analyses at the global and regional levels.
Fig. 3: Genetic pleiotropy variants between mtDNA-CN and psychiatric disorders.
Fig. 4: Functional enrichment results of expression-associated shared genes between mtDNA-CN and psychiatric disorders.

Data availability

The GWAS summary statistics for mtDNA-CN can be downloaded from https://console.cloud.google.com/storage/browser/mito-wgs-public-2023. Additionally, GWAS summary statistics for ADHD, ASD, BD, MDD, and SCZ can be accessed at https://pgc.unc.edu/for-researchers/download-results/.

Code availability

In this study, we utilized various publicly available software and tools, including the following: GPA (https://github.com/dongjunchung/GPA), PLINK (https://www.cog-genomics.org/plink/), GWAS-PW (https://github.com/joepickrell/gwas-pw), Conditional/conjunctional FDR analysis (https://github.com/precimed/pleiofdr), FUMA (https://fuma.ctglab.nl/), MetaXcan (https://github.com/hakyimlab/MetaXcan), KOBAS-i (http://bioinfo.org/kobas/).

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Acknowledgements

This work was funded by the Natural Science Foundation of China (82572306, 82072001, 82572200, 82460341), the Tianjin Municipal Major Special Project on Public Health Science and Technology (24ZXGQSY00060), the Beijing-Tianjin-Hebei Basic Research Collaboration Project (J230040), the Tianjin Natural Science Foundation (23JCZXJC00120), the Tianjin Key Medical Discipline Construction Project (TJYXZDXK-3-008C), the Science Foundation for Distinguished Young Scholars of Jiangxi Province (20242BAB23086), the GanPo Talent plan of Jiangxi Province (gpyc20240213).

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Author notes

  1. These authors contributed equally: Hui Xue, Minghuan Lei, Qiyu Zhao, Zhihui Zhang.

Authors and Affiliations

  1. Department of Radiology, Tianjin Key Lab of Functional Imaging & Tianjin Institute of Radiology, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Hui Xue, Minghuan Lei, Zhihui Zhang, Zuhao Sun, Yujie Zhang, Ying Zhai, Jinglei Xu, Ying Wang, Qi An, Wenjie Cai, Linlin Jia & Feng Liu

  2. Department of Radiology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China

    Qiyu Zhao

  3. Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin, 300222, China

    Shen Li

  4. Brain Assessment & Intervention Laboratory, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin, 300222, China

    Shen Li

  5. Department of Radiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China

    Xi-jian Dai

  6. Jiangxi Provincial Key Laboratory of Intelligent Medical Imaging, Nanchang, 330006, China

    Xi-jian Dai

  7. Nanchang Key Laboratory of Medical-Engineering Integration and Clinical Translation, Nanchang, 330006, China

    Xi-jian Dai

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  1. Hui Xue
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  2. Minghuan Lei
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  13. Shen Li
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  14. Xi-jian Dai
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Contributions

H Xue, M Lei and F Liu designed the study and wrote the manuscript; H Xue, Q Zhao, X Dai and S Li supervised research; M Lei performed the primary analyses; M Lei, Z Zhang, Z Sun and Y Zhang contributed to the interpretation of results; M Lei, Y Zhai, J Xu, Y Wang, Q An, W Cai and L Jia prepared the figures and tables; M Lei and F Liu participated in the manuscript revision. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Shen Li, Xi-jian Dai or Feng Liu.

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The authors declare no competing interests.

Ethics statement

All analyses in this study were based on publicly available GWAS datasets. Ethical approval for all GWAS datasets was obtained from the local ethics committees of the original studies, and informed consent was obtained from all participants. All methods were performed in accordance with the relevant guidelines and regulations.

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Xue, H., Lei, M., Zhao, Q. et al. Powering the mind: deciphering the shared genetic architecture between mitochondrial DNA copy number and major psychiatric disorders. Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03463-0

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