The role of mitochondrial DNA copy number in neuropsychiatric disorders: A bidirectional two-sample Mendelian randomization study

Abstract 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’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. 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.