Bidirectional Associations Between Frailty and Preeclampsia: A Two-Sample Mendelian Randomization Study

Objective: This study aims to elucidate the potential bidirectional genetic relationship between frailty and preeclampsia (PE), which currently remains unclear. Methods: We performed a bidirectional two-sample Mendelian randomization (MR) analysis to assess the causal link between the frailty index (FI) and PE. Summary statistics for FI were sourced from the IEU Open GWAS project (ebi-a-GCST90020053). For PE, two independent datasets were employed: one from IEU Open GWAS (ebi-a-GCST90018906) and another from the FinnGen R12 release (finn-b-O15_PREECLAMPS), to improve robustness and generalizability. The primary analysis used the inverse variance weighted (IVW) method, supported by MR-Egger, weighted median, simple mode and weighted mode methods. Sensitivity analyses were performed using Cochrane’s Q test, the MR-Egger intercept test, the MR-PRESSO global test and leave-one-out analysis. Results: Genetically predicted FI conferred an increased odds of PE, as robustly demonstrated by the IVW method in both independent datasets: ebi-a-GCST90018906 (OR = 3.027, 95% CI [1.445, 6.343], P = 0.003]) and finn-b-O15_PREECLAMPS (OR = 1.561, 95% CI [1.013, 2.404], P = 0.043). Conversely, PE also showed a significant causal effect on FI in the FinnGen dataset (OR = 1.047, 95% CI [1.031, 1.064], P < 0.001). These results indicate that higher genetically predicted frailty is a risk factor for PE and PE may in turn contribute to the exacerbation of frailty. The robustness of these associations was supported by consistent findings across multiple sensitivity analyses. Conclusion: This study provides suggestive genetic evidence for a potential bidirectional relationship between frailty and PE. The forward-direction findings, with frailty as the exposure and PE as the outcome, were consistently supported across two independent datasets, while the reverse-direction findings, with PE as the exposure and frailty as the outcome, were dataset-dependent and require further validation. Frailty may represent a promising target for obstetric risk stratification, pending confirmation in pregnant populations.