The role of mitochondrial DNA copy number in female infertility: a bidirectional two-sample Mendelian randomization...

Previous studies on the impact of mitochondrial DNA (mtDNA) copy number on female infertility were limited and inconsistent.

The causal relationship between mtDNA copy number and female infertility was evaluated using a bidirectional 2-sample Mendelian randomization (MR) method. Inverse variance weighted (IVW) method was applied for principal analysis, and MR-Egger, weighted median, simple mode, weighted mode method for secondary analyses. Sensitivity analysis was conducted using MR-PRESSO, MR-Egger, Cochran's Q, and leave-one-out tests. Two large-scale GWAS mtDNA copy number datasets were employed for testing and validation to ensure reliable results.

According to the forward MR analysis, genetically predicted mtDNA copy number was not associated with premature ovarian failure (POF) (OR = 1.969, 95% CI 0.571-6.789; p = .283), polycystic ovary syndrome (PCOS) (OR = 0.821, 95% CI 0.314-2.142; p = .686), endometriosis (OR = 1.281, 95% CI 0.962-1.704; p = 0.090), or female infertility (OR = 0.966; 95% CI 0.744-1.253; p = .794) but was associated with intestinal endometriosis (OR = 7.528; 95% CI 1.654-34.262; p = .009) and adenomyosis (OR = 1.710; 95% CI 1.118-2.616; p = .013). Reverse MR studies did not reveal a correlation between female infertility and mtDNA copy number. Similar results were observed in the validation data.

Our study suggested that there is no causal relationship between mtDNA copy number and female infertility, but there is a causal relationship between mtDNA copy number and intestinal endometriosis and adenomyosis. The genetic evidence provided by this study provides a new perspective for studying the impact of mtDNA copy number on female infertility.