Integrative Genetic Analyses Identify Mitochondrial-Related Genes Associated With Female Reproductive Disorders.

Abstract

Mitochondrial dysfunction has been implicated in various female reproductive disorders, but the underlying molecular links remain poorly understood. Here, we systematically investigated the genetic associations between mitochondrial-related genes and 14 female reproductive disorders through an integrative analysis of multi-omics datasets. Summary-level data on mitochondrial gene expression, DNA methylation, and protein abundance were obtained from multiple quantitative trait loci (QTL) resources and jointly analyzed in relation to 14 common female reproductive disorders. By integrating genetic association signals across molecular layers, we identified multiple mitochondrial-related genes showing nominal candidate associations with reproductive outcomes. Notably, genetically predicted NEU4 expression was nominally associated with lower risks of ovarian dysfunction and polycystic ovary syndrome. At the methylation level, NEU4 was represented by 25 probe-trait associations across six reproductive phenotypes. At the proteomic level, higher genetically predicted NUDT9 abundance was associated with abnormal uterine bleeding. Overall, 12 associations survived false discovery rate (FDR) correction, of which 10 also satisfied the heterogeneity in dependent instruments (HEIDI) threshold. ALDH2 remained a recurrent nominal and pharmacologically annotated candidate. These findings provide an exploratory molecular landscape and prioritize a smaller set of FDR-supported signals for independent replication and mechanistic investigation.