https://doi.org/10.1140/epjs/s11734-026-02369-w
Regular Article
A nomothetic systems framework for mitochondrial DNA copy number in neuropsychiatric disorders: bidirectional two-sample Mendelian randomization
1
Sichuan Provincial Center for Mental Health, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, 610072, Chengdu, China
2
Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, 610072, Chengdu, China
3
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
4
Program in Mental Health, Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
5
Cognitive Impairment and Dementia Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
6
Cognitive Fitness and Biopsychological Technology Research Unit, Faculty of Medicine, Chulalongkorn University, 10330, Bangkok, Thailand
7
Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria
8
Research Institute, Medical University of Plovdiv, Plovdiv, Bulgaria
9
Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, 02447, Seoul, Korea
a
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Received:
13
March
2026
Accepted:
27
April
2026
Published online:
20
May
2026
Abstract
Inconsistent findings characterize studies on mitochondrial DNA copy number (mtDNA-CN) and its relation to neuropsychiatric disorders. This bidirectional two-sample Mendelian Randomization (MR) study explores potential causal links between mtDNA-CN and neuropsychiatric disorders, including Alzheimer’s disease, Attention-deficit/hyperactivity disorder, Anorexia nervosa, Autism spectrum disorder (ASD), Bipolar disorder, Major depressive disorder, obsessive–compulsive disorder, schizophrenia, anxiety disorders, and post-traumatic stress disorder. Genetic associations with mtDNA-CN were drawn from the UK Biobank’s GWAS data (n = 395,718), while neuropsychiatric disorder data came from the Psychiatric Genomics Consortium and FinnGen Consortium. Three MR methods—Inverse Variance Weighting (IVW), MR-Egger, and Weighted Median—were used to establish relationships. Cochran’s Q test, MR-PRESSO, and MR-Egger’s intercept test assessed heterogeneity and pleiotropy. A leave-one-out analysis evaluated the impact of individual SNPs on MR results, and a bidirectional analysis examined the relationship between mtDNA-CN and neuropsychiatric disorders. The MR analysis indicated a causal relationship between mtDNA-CN and ASD using the IVW method (OR = 0.735, 95% CI: 0.597–0.905; P = 0.004). Conversely, a causal relationship was identified between anxiety disorders and mtDNA-CN (β = 0.029, 95% CI: 0.010–0.048; P = 0.003). No causal associations were found for other disorders. Sensitivity tests corroborated the robustness of these findings. In this study, we demonstrated genetically predicted associations between mtDNA-CN and both ASD and anxiety disorders, which are consistent with a possible causal effect. These findings reflect higher-order interactions within biological systems, suggesting that mitochondrial self-organization plays a role in the pathophysiology of ASD, while mtDNA-CN serves as a responsive biomarker in anxiety disorders within a complex systems framework.
Supplementary Information The online version contains supplementary material available at https://doi.org/10.1140/epjs/s11734-026-02369-w.
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© The Author(s), under exclusive licence to EDP Sciences, Springer-Verlag GmbH Germany, part of Springer Nature 2026
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
