Wan XiaoJu, Lai XiaoBao, Huang MeiZhen, Yu Min, Ding Tao, Huang ZhiHui, Zhang ZhiQin, Wu XingWu, Tan Jun
Reproductive Medicine Center, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, China.
Gynecol Endocrinol. 2024 Dec;40(1):2444380. doi: 10.1080/09513590.2024.2444380. Epub 2024 Dec 23.
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; = .283), polycystic ovary syndrome (PCOS) (OR = 0.821, 95% CI 0.314-2.142; = .686), endometriosis (OR = 1.281, 95% CI 0.962-1.704; = 0.090), or female infertility (OR = 0.966; 95% CI 0.744-1.253; = .794) but was associated with intestinal endometriosis (OR = 7.528; 95% CI 1.654-34.262; = .009) and adenomyosis (OR = 1.710; 95% CI 1.118-2.616; = .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.
先前关于线粒体DNA（mtDNA）拷贝数对女性不孕症影响的研究有限且结果不一致。
采用双向双样本孟德尔随机化（MR）方法评估mtDNA拷贝数与女性不孕症之间的因果关系。主要分析采用逆方差加权（IVW）法，次要分析采用MR-Egger、加权中位数、简单模式、加权模式法。使用MR-PRESSO、MR-Egger、 Cochr an's Q和留一法检验进行敏感性分析。采用两个大规模全基因组关联研究（GWAS）的mtDNA拷贝数数据集进行测试和验证，以确保结果可靠。
根据正向MR分析，基因预测的mtDNA拷贝数与卵巢早衰（POF）（比值比[OR]=1.969，95%置信区间[CI]0.571-6.789；P=.283）、多囊卵巢综合征（PCOS）（OR=0.821，95%CI0.314-2.142；P=.686）、子宫内膜异位症（OR=1.281，95%CI0.962-1.704；P=0.090）或女性不孕症（OR=0.966；95%CI0.744-1.253；P=.
