Advancing our understanding of genetic risk factors and potential personalized strategies for pelvic organ prolapse

Although pelvic organ prolapse is a common gynecological condition, the genetic component of disease risk is not well known. Here the authors find common genetic variants associated with the disease and present a polygenic risk score to enhance individual risk prediction. Pelvic organ prolapse is a common gynecological condition with limited understanding of its genetic background. In this work, we perform a genome-wide association meta-analysis comprising 28,086 cases and 546,291 controls from European ancestry. We identify 19 novel genome-wide significant loci, highlighting connective tissue, urogenital and cardiometabolic as likely affected systems. Here, we prioritize many genes of potential interest and assess shared genetic and phenotypic links. Additionally, we present the first polygenic risk score, which shows similar predictive ability (Harrell C-statistic (C-stat) 0.583, standard deviation (sd) = 0.007) as five established clinical risk factors combined (number of children, body mass index, ever smoked, constipation and asthma) (C-stat = 0.588, sd = 0.007) and demonstrates a substantial incremental value in combination with these (C-stat = 0.630, sd = 0.007). These findings improve our understanding of genetic factors underlying pelvic organ prolapse and provide a solid start evaluating polygenic risk scores as a potential tool to enhance individual risk prediction.