Proteome-wide Mendelian randomization and functional studies uncover therapeutic targets for polycystic ovarian syndrome

作者：Fei-Da Ni, Feixia Wang, Jing Sun, Mixue Tu, Jianpeng Chen, Xiling Shen, Xiaohang Ye, Ruixue Chen, Yifeng Liu, Xiao Sun, Jianhua Chen, Xue Li, Dan Zhang · 发表于：The American Journal of Human Genetics · 年份：2024 · DOI：10.1016/j.ajhg.2024.10.008 · 被引用次数：14 · 研究领域：Ovarian function and disorders、Genetic Associations and Epidemiology、Reproductive Biology and Fertility

Polycystic ovarian syndrome (PCOS) is an endocrine syndrome that affects a large portion of women worldwide. This proteogenomic and functional study aimed to uncover candidate therapeutic targets for PCOS. We comprehensively investigated the causal association between circulating proteins and PCOS using two-sample Mendelian randomization analysis. Cis-protein quantitative trait loci were derived from six genome-wide association studies (GWASs) on plasma proteome. Genetic associations with PCOS were obtained from a large-scale GWAS meta-analysis, FinnGen cohort, and UK Biobank. Colocalization analyses were performed to prioritize the causal role of candidate proteins. Protein-protein interaction (PPI) and druggability evaluation assessed the druggability of candidate proteins. We evaluated the enrichment of tier 1 and 2 candidate proteins in individuals with PCOS and a mouse model and explored the potential application of the identified drug target. Genetically predicted levels of 65 proteins exhibited associations with PCOS risk, with 30 proteins showing elevated levels and 35 proteins showing decreased levels linked to higher susceptibility. PPI analyses revealed that FSHB, POSTN, CCN2, and CXCL11 interacted with targets of current PCOS medications. Eighty medications targeting 20 proteins showed their potential for repurposing as therapeutic targets for PCOS. EGLN1 levels were elevated in granulosa cells and the plasma of individuals with PCOS and in the plasma and ovaries ...