Metabolome-wide Mendelian randomization assessing the causal relationship between blood metabolites and primary ovarian insufficiency.

Background & aims: Primary ovarian insufficiency (POI) is a significant clinical syndrome that leads to female infertility, and its incidence continues to increase. We used metabolome-specific Mendelian randomization (MR) to identify causally associated metabolites and explore the relationship between candidate metabolites and upstream genetic variations.

Methods: The primary MR analysis utilized the inverse variance weighted (IVW) method as the primary approach to assess the causal relationship between exposure and POI. Multiple sensitivity analyses included MR-Egger, weighted median, and weighted mode methods.

Results: After using genetic variants as probes, we identified 27 metabolites of 278 that are associated with the risk of POI, including dodecanedioate (OR 0.052, 95 % CI 0.010-0.265; P < 0.001), adrenate (OR 0.113, 95 % CI 0.016-0.822; P = 0.031), indolepropionate (OR 0.174, 95 % CI 0.051-0.593; P = 0.005), homocitrulline (OR 0.194, 95 % CI 0.051-0.741; P = 0.016), and 3-methylhistidine (OR 0.404, 95 % CI 0.193-0.848; P = 0.017). Our study indicated the presence of heterogeneity; therefore, we employed the IVW random-effects model as the primary approach. KEGG pathway enrichment analysis identified six significant metabolic pathways, primarily including biosynthesis of unsaturated fatty acids, phenylalanine, tyrosine and tryptophan biosynthesis, aminoacyl-tRNA biosynthesis, linoleic acid metabolism, valine, leucine and isoleucine biosynthesis, ubiquinone and other terpenoid-quinone biosynthesis.

Conclusions: By integrating genomics and metabolomics, this study provides novel insights into the causal relationship linking circulating metabolites and the onset of POI.