Univariable and multivariable Mendelian randomization investigating the effects of telomere length on the risk of adverse pregnancy outcomes

Abstract

Background: Numerous observational studies have revealed a correlation between telomere length (TL) and adverse pregnancy outcomes (APOs). However, the impacts of TL on APOs are still unclear.

Methods: Mendelian randomization (MR) was carried out using summary data from genome-wide association studies (GWAS). Inverse variance weighted (IVW) was employed as the primary analysis to explore the causal relationship between TL and APOs. The exposure data came from a GWAS dataset of IEU analysis of the United Kingdom Biobank phenotypes consisting of 472,174 European participants. Summary-level data for five APOs were obtained from the GWAS datasets of the FinnGen consortium. We also performed multivariate MR (MVMR), adjusting for smoking, alcohol intake, body mass index (BMI), and number of live births. In addition, we conducted a series of rigorous analyses to further examine the validity of our MR findings.

Results: After Bonferroni correction and rigorous quality control, univariable MR (UVMR) demonstrated that a shorter TL was significantly associated with an increased risk of spontaneous abortion (SA) (odds ratio [OR]: 0.815; 95% confidence interval [CI]: 0.714-0.930; P = 0.002) and preterm birth (PTB) (OR: 0.758; 95% CI: 0.632-0.908; P = 0.003) in the IVW model. There was a nominally significant relationship between TL and preeclampsia (PE) in the IVW model (OR: 0.799; 95% CI: 0.651-0.979; P = 0.031). However, no significant association was found between TL and gestational diabetes mellitus (GDM) (OR: 0.950; 95% CI: 0.804-1.122; P = 0.543) or fetal growth restriction (FGR) (OR: 1.187; 95% CI: 0.901-1.565; P = 0.223) among the five statistical models. Furthermore, we did not find a significant causal effect of APOs on TL in the reverse MR analysis. MVMR analysis showed that the causal effects of TL on SA remained significant after accounting for smoking, alcohol intake, BMI, and number of live births.

Conclusion: Our MR study provides robust evidence that shorter telomeres were associated with an increased risk of SA. Further work is necessary to investigate the potential mechanisms. UVMR and MVMR findings showed limited evidence that TL affects the risk of PTB, PE, GDM, and FGR, illustrating that the outcomes of previous observational studies may have been confounded.

Keywords: Mendelian randomization; adverse pregnancy outcomes; causality; preterm birth; spontaneous abortion; telomere length.