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.