Multiomic insight into the involvement of cell aging related genes in the pathogenesis of endometriosis

Endometriosis significantly impacts women's health and fertility, with cell aging playing a crucial role in its development. This study utilized a multi-omic summary Mendelian randomization (SMR) analysis, integrating genome-wide association studies (GWAS), expression quantitative trait loci (eQTLs), methylation quantitative trait loci (mQTLs), and protein quantitative trait loci (pQTLs). The goal was to identify genes that exhibit causal associations between cell aging and endometriosis. Validation was conducted using the FinnGen R10 and UK Biobank cohorts. The SMR and HEIDI tests evaluated the genetic variants linked to both cell aging and endometriosis risk. Colocalization analysis revealed shared genetic variants, uncovering significant associations between the two conditions. A total of 196 CpG sites in 78 genes, alongside 18 eQTL-associated genes and 7 pQTL-associated proteins, were identified. Notably, the MAP3K5 gene displayed contrasting methylation patterns linked to endometriosis risk. In validation cohorts, the THRB gene and ENG protein were confirmed as risk factors. The findings suggest a causal mechanism where specific methylation patterns downregulate the MAP3K5 gene, heightening endometriosis risk, highlighting it and associated pathways as potential therapeutic targets.