Mitochondrial DNA Copy Number and Risk of Gestational Metabolic Disorders: A Two‐Sample Mendelian Randomization Study

Background Mitochondrial DNA copy number (mtDNA‐CN) has been implicated in gestational metabolic disorders (GMD), yet their causal relationships remain unclear. This study employed genetic approaches to investigate potential causal associations between mtDNA‐CN and various GMDs. Methods We conducted a two‐sample Mendelian randomization (MR) analysis utilizing genome‐wide association study (GWAS) summary statistics from large‐scale populations: mtDNA‐CN ( n = 395 718), preeclampsia (PE) ( n = 267 242), gestational diabetes mellitus (GDM) ( n = 123 579), gestational hypertension (GH) ( n = 118 990), hyperlipidemia ( n = 9714), and obesity ( n = 463 010). Independent single‐nucleotide polymorphisms (SNPs) were rigorously selected as instrumental variables (IVs) following stringent criteria. The primary analysis employed the fixed‐effects inverse variance weighted (IVW) method. Multiple sensitivity analyses, including leave‐one‐out analysis, Cochran's Q test, and MR‐Egger regression, were conducted to assess the robustness of our findings. Results The IVW analysis revealed a significant protective association between increased mtDNA‐CN and PE risk (OR = 0.6262, 95% CI: 0.4201–0.9335, p = 0.0283). However, no significant associations were observed between mtDNA‐CN and other GMDs (all p > 0.05). Sensitivity analyses, including MR‐Egger regression, showed no evidence of horizontal pleiotropy (all p > 0.05), supporting the robustness of our findings. Conclusion This genetic investigation provides compelling evidence for a potentially protective effect of higher mtDNA‐CN against PE development. These findings not only suggest mtDNA‐CN as a promising biomarker for PE risk assessment but also offer novel insights into the biological mechanisms underlying PE, potentially informing future preventive strategies and therapeutic interventions.