The mitochondrial DNA copy number and ovary-related reproductive disorders: A bidirectional two-sample Mendelian randomization study.

OBJECTIVE

In the present study, a bidirectional two-sample Mendelian randomization approach was utilized to explore potential causal relationships between mitochondrial DNA copy number (mtDNA-CN) and ovary-related reproductive disorders (ORRDs), including ovarian dysfunction, ovarian cyst, polycystic ovary syndrome (PCOS), premature ovarian failure (POF) and ovarian endometriosis.

METHODS

Genetic associations with mtDNA-CN were obtained from three genome-wide association study (GWAS) summary statistics from the UK Biobank, and ORRD data were investigated using summary statistics from the FinnGen cohort. Single nucleotide polymorphisms (SNPs) correlated with mtDNA-CN were selected as genetic instrumental variables (IVs) to estimate the causal effect of mtDNA-CN on ORRDs using the inverse-variance weighted (IVW) method with heterogeneity and pleiotropy analysis, and we repeated this in the opposite direction using instruments for ORRDs.

RESULTS

We found that the genetically predicted mtDNA was indicative of increased levels of PCOS (OR = 1.16; P < 0.001) and ovarian endometriosis (OR = 1.25; P = 0.007) in the IVW analysis and was not associated with the risk of other ORRDs. In the reverse direction, genetically predicted ORRDs were not associated with mtDNA-CN levels in the IVW analysis. Sensitivity and replication analyses showed the results to be stable.

CONCLUSION

We found that mtDNA-CN may increase the risk of PCOS and ovarian endometriosis. This may have implications for mtDNA-CN as a biomarker for these conditions in clinical practice.