Development of a polygenic risk score for pelvic organ prolapse in Chinese women

Pelvic organ prolapse (POP), a condition whose development is shaped by both genetic and clinical risk factors, significantly impairs women's quality of life, yet genetic insights into non-European populations and comprehensive risk models that integrate genetic and clinical data remain insufficiently explored. To address this gap, the first polygenic risk score (PRS) for POP in the Chinese population was constructed, leveraging 20 disease-associated genetic variants derived from the largest available genome-wide association study (GWAS) on POP. The research analyzed two cohorts: a discovery cohort comprising 576 POP cases and 623 controls, and a validation cohort with 264 cases and 200 controls. Results confirmed that the POP case group had a significantly higher PRS than the control group; notably, women in the top 10% of PRS values (highest genetic risk) had an odds ratio of 2.6 for developing POP compared to those in the bottom 10% (lowest genetic risk). A high PRS was also found to correlate significantly with POP occurrence in specific subgroups: women over 50 years old and those with one or no childbirths. Additionally, an integrated prediction model combining PRS with clinical risk factors demonstrated better predictive accuracy than existing PRS-only models. This combined risk assessment tool proves robust for POP risk prediction and stratification, providing valuable guidance for personalized preventive measures and treatment strategies in future clinical practice.

The significance of this work lies in its focus on understudied non-European populations, as most prior POP genetic research has centered on European cohorts - limiting the applicability of findings to diverse ethnic groups like the Chinese. By utilizing 20 GWAS-identified POP-associated variants, the PRS was tailored to capture genetic susceptibility relevant to Chinese women, addressing a critical gap in global POP research. The two-cohort design (discovery and validation) strengthened the reliability of results: the discovery cohort allowed for initial PRS construction and association testing, while the validation cohort confirmed that the PRS effectively distinguished cases from controls across independent samples, ensuring the score's generalizability within the Chinese population.

Key findings from the cohort analyses highlight the PRS's ability to stratify POP risk. The 2.6-fold higher odds ratio in the top 10% PRS group versus the bottom 10% underscores the substantial role of genetic factors in POP development - even when accounting for other influences. Subgroup analyses further refined this understanding, revealing that genetic risk (as measured by PRS) is particularly impactful in older women (over 50) and those with minimal or no childbirth history. For women over 50, age-related changes in pelvic floor muscle strength and connective tissue elasticity may interact with genetic susceptibility to increase POP risk; in women with few or no childbirths, the absence of childbirth-related pelvic trauma suggests genetics play a more prominent role in driving disease onset, compared to those with a history of vaginal delivery (where clinical factors like labor-related damage may be more dominant).

The integration of PRS with clinical risk factors represents a major advancement over existing models. Traditional POP risk assessment relies heavily on clinical variables such as age, parity (number of childbirths), body mass index (BMI), and history of pelvic surgery - factors that capture environmental and lifestyle influences but overlook genetic susceptibility. By combining PRS with these clinical factors, the integrated model offers a more holistic view of POP risk, as it accounts for both inherited predispositions and modifiable or situational factors. This enhanced predictive accuracy is critical for clinical practice, as it enables more precise identification of women at high risk - avoiding the limitations of models that rely solely on genetics (which may miss clinically driven cases) or clinical factors (which may underestimate genetically susceptible individuals).

The practical implications of this combined model are far-reaching. For preventive care, it can help clinicians identify high-risk women early - for example, a 45-year-old woman with a high PRS and a family history of POP might be advised on pelvic floor exercises or lifestyle modifications (such as weight management) to reduce her risk of developing symptoms later in life. For treatment, risk stratification can guide personalized approaches: women with a high PRS and mild POP may benefit from more frequent monitoring, while those with both high genetic risk and severe clinical factors (e.g., multiple childbirths) might be considered for earlier intervention. Additionally, the PRS provides a foundation for further research into POP's genetic mechanisms in Chinese women, potentially leading to the discovery of new therapeutic targets or more refined risk scores in the future.

Overall, this research not only fills a gap in non-European POP genetic research but also delivers a practical, accurate tool for clinical risk assessment. By bridging genetic and clinical data, the combined model advances personalized medicine for POP, offering hope for improved prevention and treatment outcomes for Chinese women affected by this common, quality-of-life-impacting condition.