Spatially Constrained Gene Regulation Identifies Key Genetic Contributions of Preeclampsia, Hypertension, and Proteinuria†

Preeclampsia (PE) is a relatively common but severe pregnancy disorder (with very limited effective treatments) characterized by hypertension (HTN) and usually proteinuria (PRO) or other organ damage. Genome-wide association studies (GWAS) of PE, HTN, and PRO have mostly identified risk loci single nucleotide polymorphisms (SNPs) located in noncoding genomic regions, likely impacting the regulation of distal gene expression. The latest GWAS associated (P < 1 × 10-6) SNPs to PE (n = 25), HTN (n = 1926), and PRO (n = 170). Our algorithmic analysis (CoDeS3D) used chromatin connection data (Hi-C) derived from 70 cell lines followed by analysis of two expression quantitative trail loci (eQTL) cohorts: GTEx (838 donors, 54 tissues, totaling 15 253 samples) and DICE (91 donors, 13 blood tissue types). We identified spatially constrained eQTLs which implicate gene targets in PE (n = 16), HTN (n = 3561), and PRO (n = 335). By overlapping these target genes and their molecular pathways (protein-protein interaction networks), we identified shared functional impacts between PE and HTN, which are significantly enriched for regulatory interactions which target genes intolerant to loss-of-function mutations. While the disease-associated SNP loci mostly do not overlap, the regulatory signals (target genes and pathways) overlap, informing on PE risk mechanisms. This demonstrates a model in which genetic predisposition to HTN and PRO lays a molecular groundwork toward risk for PE pathogenesis. This overlap at the gene regulatory network level identifies possible shared therapeutic targets for future study.