Background. 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. Methods. 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 Q test, MR-PRESSO, and MR-Egger 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. Results. The MR analysis indicated a causal relationship between mtDNA-CN and ASD using the IVW method (OR = 0.735,95%CI:0.597 to 0.905; P = 0.004). Conversely, a causal relationship was identified between Anxiety disorders and mtDNA-CN (β= 0.029,95%CI:0.010 to 0.048; P = 0.003). No causal associations were found for other disorders. Sensitivity tests corroborated the robustness of these findings. Conclusion. In this study, potential causal relationships between mtDNA-CN and both ASD and Anxiety disorders were established. These findings provide insights into the biological mechanisms of mtDNA-CN on ASD and underscore the significance of mtDNA copy number as a potential biomarker for Anxiety disorders.

The authors have declared no competing interest.

There was no specific funding for this specific study.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Our analyses were based on publicly available data that had been approved by relevant review boards. Therefore, no additional ethical approval is required.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The datasets used and/or analyzed during the current study are presented in the manuscript. Summary statistics for GWAS are publicly available.