Causal relationships between mitochondrial DNA copy number and hypertensive disorders in pregnancy: A Mendelian randomization study

Introduction: The association between mitochondrial DNA (mtDNA) copy number and hypertensive disorders in pregnancy has been explored in several observational studies; however, due to methodological limitations and confounding factors, consistent conclusions have not been reached. Objectives: This study aimed to determine whether genetically predicted mtDNA copy number has a causal effect on the risk of hypertensive disorders in pregnancy using Mendelian randomization (MR) analysis. Methods: MR analyses were performed to assess genetic relationships and potential causal associations among four hypertensive pregnancy outcomes: Pre-existing hypertension complicating pregnancy, gestational hypertension, pre-eclampsia or eclampsia (POE), and pre-eclampsia (PE). The mtDNA copy number for each outcome was obtained from genome-wide association study datasets. The primary MR method was inverse variance weighting (IVW), supported by four complementary approaches (MR-Egger, weighted median, simple mode, and weighted mode) to ensure robust inference. Results: IVW analysis revealed a significant inverse correlation between mtDNA copy number and both POE (odds ratio [OR] 95% confidence interval [CI] = 0.738 [0.578 – 0.943]; p=0.015) and PE (OR [95% CI] = 0.735 [0.563 – 0.960]; p=0.024), suggesting a protective effect of higher mtDNA copy number. Conclusion: This MR investigation demonstrates a positive causal relationship between higher mtDNA copy number and reduced risk of PE and related hypertensive disorders in pregnancy.