Investigating genetic links between biological aging and adverse pregnancy outcomes

Observational studies suggest a link between biological aging and adverse pregnancy outcomes (APOs), but causal relationships remain unclear. This study aimed to investigate the relationship between genetically predicted biological aging traits and APOs. Genetic summary statistics from the genome-wide association study (GWAS) of the IEU open GWAS, FinnGen, and meta-analysis were analyzed using Mendelian randomization (MR) to infer causality. Biological aging indicators included facial aging, frailty index, and epigenetic aging markers. APOs included gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HTP), preterm birth (PTB), and pregnancy loss (PL). The primary MR analyses utilized the inverse variance weighted method, followed by sensitivity analyses. Reverse MR and multivariable MR were employed to explore reverse causality and potential mediating effects. We found that the frailty index was positively associated with GDM (OR = 2.00, 95% CI 1.44-2.77, P = 3.41E - 5), HTP (OR = 2.09, 95% CI 1.33-3.29, P = 0.001), and PL (OR = 1.22, 95% CI 1.03-1.46, P = 0.023) risks. Inverse MR showed that susceptibility to HTP (β = 0.05, 95% CI 0.03-0.07, P = 4.43E - 6) and PL (β = 0.06, 95% CI 0.01-0.11, P = 0.011) was positively correlated with the frailty index, while PTB was positively correlated with PhenoAge (β = 0.24, 95% CI 0.02-0.46, P = 0.035). Our findings suggest a genetic association between the frailty index and susceptibility to GDM, HTP, and PL. Closer monitoring of biological aging indicators during pregnancy may be necessary to prevent APOs.