Genetic Correlation and Causal Inference Between Female Fat Distribution and Preeclampsia: An Integrative Genomic Study

ABSTRACT

Preeclampsia (PE) is a major cause of maternal and perinatal morbidity. Because abnormal fat distribution is closely related to metabolic dysfunction, vascular injury, and hypertensive disorders during pregnancy, clarifying its genetic relationship with PE may improve our understanding of adverse pregnancy outcomes. Here, we investigated the shared genetic architecture between PE and waist–hip ratio adjusted for body mass index (WHRadjBMI) by integrating large‐scale genome‐wide association study (GWAS) summary statistics for female WHRadjBMI from the GIANT consortium ( n  ≈ 700 000) and PE from FinnGen R11 (7955 cases and 124 764 controls). Analyses included genome‐wide genetic correlation, polygenic overlap, local genetic correlation, cross‐trait GWAS meta‐analysis, tissue/cell type enrichment, functional annotation, and Mendelian randomization, using tools including linkage disequilibrium score regression (LDSC), MiXeR, LAVA, ρ‐HESS, MTAG, CPASSOC, and conjunctional false discovery rate (conjFDR). We identified approximately 0.5 k shared causal variants; MiXeR detected a modest but significant polygenic overlap (rg = 0.08, p  = 0.006), whereas LDSC showed no significant genome‐wide correlation. A shared genetic locus near MTHFR‐CLCN6 (rs17367504) was detected, consistent with known PE biology. Enrichment analyses implicated VEGFA‐driven vascular and immune processes, with uterine pericytes displaying the strongest shared cell‐type enrichment. Mendelian randomization supported a causal effect of WHRadjBMI on PE (IVW: p  = 2.7 × 10 ⁻⁴ ) but not reverse causation. These findings suggest that genetically predicted fat distribution may contribute to PE susceptibility and highlight shared vascular–immune pathways that may link WHR‐related genetic risk to pregnancy complications.