Placental weight as a predictor of future health: Insights from a large-scale genome-wide association study

Introduction

Placental weight has been associated with various adult-onset diseases, but the causal relationships and underlying mechanisms remain unclear.

Methods

This two-sample Mendelian randomization (MR) study utilized genome-wide association study (GWAS) data from multiple independent cohorts, primarily of European ancestry. The analysis included over 1.8 million individuals for type 2 diabetes mellitus (T2DM) outcomes. Data from four independent cohorts were used for validation. The inverse variance-weighted method was used for primary analysis, with weighted median, weighted mode, and MR-Egger regression for sensitivity analyses.

Results

Each standard deviation increase in genetically predicted placental weight was associated with T2DM (β = −0.109, 95 % CI: −0.184 to −0.034), basal cell carcinoma (β = 0.130, 95 % CI: 0.016 to 0.245), acute upper respiratory infections (β = −0.062, 95 % CI: −0.113 to −0.011), neurological diseases (β = −0.009, 95 % CI: −0.014 to −0.003), and endometrial cancer (β = −0.561, 95 % CI: −0.961 to −0.161). Placental weight also showed significant negative associations with blood glucose levels (β = −0.102, 95 % CI: −0.200 to −0.004). Mediation analyses revealed that dried fruit intake mediated 14.68 % of the total effect on T2DM risk, while immune cell phenotype analysis identified HLA DR on CD33dim HLA DR + CD11b + as a potential mediator in the causal pathway.

Conclusion

This study provides genetic evidence for a causal relationship between placental weight and T2DM risk, mediated partly through dietary habits and immune pathways. These findings suggest that early-life placental development may influence long-term metabolic health, highlighting the importance of prenatal care in preventing adult-onset diseases.