Causal relationship between gestational diabetes and preeclampsia: A bidirectional mendelian randomization analysis

Area of Science:

• Obstetrics and Gynecology
• Genetics
• Epidemiology

Background:

• Gestational diabetes mellitus (GDM) and preeclampsia (PE) are significant pregnancy complications.
• The etiological relationship between GDM and PE remains incompletely understood.
• Bidirectional causality between these conditions warrants further investigation.

Purpose of the Study:

• To investigate the potential causal relationship between GDM and PE using a bidirectional Mendelian randomization (MR) approach.
• To explore genetic underpinnings and molecular pathways connecting GDM and PE.
• To enhance understanding of the pathogenesis of these complex pregnancy disorders.

Main Methods:

• Bidirectional Mendelian randomization (MR) analysis utilizing genome-wide association study (GWAS) data for GDM and PE from the FinnGen consortium.
• Application of various MR methods including inverse-variance weighted (IVW) and MR-Egger regression.
• Complementary knowledge-based approach to identify key genes and pathway analysis, including tissue enrichment and gene expression analysis.

Main Results:

• No significant causal effect of GDM on PE was detected (IVW OR: 1.04, 95% CI: 0.96-1.14, p=0.275).
• A significant causal effect of PE on GDM was identified (IVW OR: 1.14, 95% CI: 1.06-1.23, p<0.001).
• Twenty key genes, including ASAP2, were implicated in the PE-GDM relationship, with lower ASAP2 placental expression observed in PE patients.

Conclusions:

• The findings provide genetic evidence supporting a causal link from preeclampsia to gestational diabetes mellitus.
• This study elucidates the interconnected pathogenesis of PE and GDM.
• Genetic insights, particularly regarding ASAP2, offer a deeper comprehension of these pregnancy complications.