Decoding the genetic architecture of women reproductive aging: multi-omic integration identifies novel loci and mechanistic pathways for precision intervention

Currently, little is understood about the genetic architecture underlying Genome-wide association study (GWAS)-related traits that influence the reproductive ageing of women. To address this knowledge gap, we estimated causal single nucleotide polymorphisms (SNPs) independent of variation in the reproductive of women via genomic structural equation modelling and multiple post-GWAS methodologies. This approach led to the identification of 99 genome-wide significant loci. Next, we employed various transcriptome-wide association methods to analyse highly correlated susceptibility gene signal loci and their associated regulatory elements in relation to a GWAS of reproductive ageing in women. These analyses were integrated at the tissue, cellular, and genomic element levels. Additionally, we evaluated the significant correlations between 1,200 identified susceptibility factors and the GWAS signals relevant to the reproductive ageing of women. The polygenic scores obtained through summary statistics were further used to clarify the risk evidence of different chromosomes based on structural equations and their relationship with the reproductive ageing of women. Through the analysis of a GWAS that did not directly measure phenotypes, our study provides for the first time a comprehensive characterization of the genetic structure of the reproductive ageing of women.