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Published on: October 25, 2024
Noninvasive markers for warning premature ovarian insufficiency: a Mendelian randomisation study
Hangjing Tan1,2, Jing Zhao1,2, Baisheng Wang3,4
1Department of Reproductive Medicine, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China.
Insights
This study identifies novel noninvasive warning markers for premature ovarian insufficiency (POI) using Mendelian randomization. These findings aid in early POI detection and provide crucial fertility guidance for patients.
Area of Science:
- Genetics and Genomics
- Reproductive Biology
- Biomarker Discovery
Background:
- Premature ovarian insufficiency (POI) diagnosis and management rely on early detection and delivery.
- Current noninvasive markers for POI are limited, highlighting an urgent need for new diagnostic tools.
Purpose of the Study:
- To identify novel, noninvasive warning markers for premature ovarian insufficiency (POI).
- To explore potential underlying mechanisms of POI through pathway analysis.
Main Methods:
- Utilized two-sample Mendelian randomization (MR) with GWAS summary statistics from the FinnGen database.
- Integrated multi-omics data including metabolome, plasma proteins, gut microbiota, immunophenotypes, and microRNAs (miRNAs).
- Employed inverse variance weighted (IVW) as the primary MR method and SMR with eQTL data; identified hub genes and analyzed pathways.
Main Results:
- Identified specific metabolites, circulating plasma proteins, gut microbiota, immunophenotypes, and 23 miRNAs as potential POI warning markers.
- Three hub genes (ESR1, ERBB2, GART) were identified as significant.
- Pathway enrichment analysis suggested involvement of glutathione metabolism and the PI3 kinase pathway in POI pathogenesis.
Conclusions:
- This research presents the first identification of noninvasive POI predictors using MR.
- These novel markers offer significant potential for early POI detection and improved fertility guidance in clinical practice.
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
