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

Abstract

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

Methods: 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.

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.

Conclusions: 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.