Noninvasive markers for warning premature ovarian insufficiency: a Mendelian randomisation study

Early diagnosis and early delivery are the main strategies for the treatment of premature ovarian insufficiency (POI). However, POI warning markers, especially those that can be detected through noninvasive methods, are very limited; therefore, the identification of noninvasive markers for POI is urgent.

We acquired POI GWAS summary statistics from the FinnGen database. The metabolome, circulating plasma proteins, gut microbiota, immunophenotypes, circulating microRNAs (miRNAs), and two proteomes were obtained for two-sample Mendelian randomization (MR). Specifically, we employed inverse variance weighted (IVW) as the main method to calculate the MR effect estimates. eQTL data (from the eQTLGen Consortium) were employed for SMR. Hub genes were identified using the String database and Cytoscape software. Potential mechanisms of POI were identified via pathway enrichment analysis of the identified genes and miRNAs.

Three metabolites (sphinganine-1-phosphate levels, X-23636 levels, 4-methyl-2-oxopentanoate levels), two circulating plasma proteins (fibroblast growth factor 23 levels, neurotrophin-3 levels), one gut microbiota (faecalibacterium abundance), one immunophenotype (HVEM on naive CD8 + T cells), 23 miRNAs (miR-500a-3p, miR-555, miR-584-5p, miR-642a-5p, miR-671-3p, miR-1324, miR-6870-3p, miR-1468-5p, miR-146a-3p, miR-221-3p, miR-3121-5p, miR-3184-3p, miR-3185, miR-335-5p, miR-4302, miR-4506, miR-6808-5p, miR-6894-5p, miR-145-5p, miR-149-3p, miR-23a-3p, miR-3141, and miR-374b-5p), and three hub genes (ESR1, ERBB2, and GART) serve as warning markers for POI. Enrichment analysis indicated that pathways such as glutathione metabolism and the PI3 kinase pathway may be involved in mechanisms regulating POI.

Our results are the first to identify noninvasive predictors for POI via MR, providing contributions for early warning and fertility guidance for clinical POI patients.