Causal associations between plasma proteins and premature ovarian failure through multi-omics Mendelian randomization...

Premature ovarian failure (POF), an endocrine disorder with ovarian dysfunction before age 40 years, severely affects fertility and health. This study aims to elucidate the genetic association of POF through plasma protein profiling to identify potential therapeutic targets.

Using genetic instruments derived from the UKB-PPP and eQTLGen, two-sample Mendelian randomization (MR) analysis was conducted to systematically identify significant causal associations between plasma proteins and POF at both the gene expression and protein levels. Additional analytical approaches, including summary-data-based MR (SMR), heterogeneity in dependent instruments (HEIDI) testing, Bayesian co-localization, and a series of sensitivity analyses, were also employed to further validate the robustness of the findings. Subsequently, mediation analysis was performed to explore potential pathways through which plasma proteins may influence POF via immune or metabolic intermediaries. Finally, a phenome-wide MR analysis (MR-PheWAS) was conducted to assess the potential pleiotropic effects of the identified proteins.

Our analysis identified 96 proteins exhibiting causal relationship with POF. Notably, C-C motif chemokine 23 (CCL23) and tumor necrosis factor receptor superfamily member 14 (TNFRSF14) emerged as protective factors. Validation through SMR and HEIDI tests confirmed significant associations for 58 proteins. Bayesian colocalization further provided moderate evidence of colocalization for CCL23 [posterior probability for H4 (PP.H4) =72.1%] and TNFRSF14 (PP.H4 =54.9%). Additionally, mediation analysis revealed that immune cell traits and metabolic factors play crucial roles in POF development. MR-PheWAS demonstrated that CCL23 and TNFRSF14 are associated with various phenotypes, suggesting their broader implications beyond POF.

This study identifies CCL23 and TNFRSF14 as putative causal mediators of POF, revealing their potential as dual therapeutic targets and providing novel insights into the underlying mechanisms of POF.