Regulatory Genomics of Preeclampsia-Specific Risk Variants Highlights Immune and Endothelial Mechanisms

Abstract

BackgroundPreeclampsia (PE) is a complex hypertensive disorder of pregnancy characterized by endothelial dysfunction, immune dysregulation, and systemic vascular injury. Multiple genome-wide association studies (GWAS) have revealed genetic signals shared with hypertension and blood pressure traits, potentially obscuring biological mechanisms that are more specific to PE pathogenesis. Furthermore, the functional consequences of most PE-associated variants remain poorly understood. In addition, GWAS relies on short-read sequencing and array-based analyses, limiting the ability to identify insertions, deletions, and other structural variants that may contribute to disease-associated regulatory mechanisms. In this study, we investigated the regulatory architecture of PE-specific genetic variants and evaluated their potential linkage disequilibrium (LD) with structural variants. MethodsWe integrated GWAS, transcriptomic, and long-read sequencing data to investigate the regulatory architecture of PE-specific genetic variants. Summary statistics for PE, hypertension, systolic and diastolic blood pressure were obtained from the GWAS Catalog, and variants uniquely associated with PE (P [≤] 1x10-4) were prioritized. Cis-expression quantitative trait locus (cis-eQTL) analyses were performed in whole-blood RNA-sequencing data from 180 African American women. Significant associations were replicated in biologically relevant tissues from the GTEx Project, including vascular, renal, and immune-related tissues. Long-read sequencing-derived structural variants (SVs) were subsequently evaluated for LD with replicated eQTL loci. ResultsA total of 10,843 PE-specific variants, present in whole-genome sequencing data of the 180 women, were evaluated. Cis-eQTL analyses identified 480 significant eQTL-gene associations involving 277 unique variants and 192 genes (FDR [≤] 0.05). Replication analyses supported 69 eQTL-gene associations across five GTEx tissues, involving 35 variants and 14 genes. Replicated signals were enriched in vascular tissues, particularly artery tibial and artery aorta. Several prioritized genes converged on immune and vascular pathways, including MICA, HLA-DPB1, SEMA4D, JUP, ZFP57, and TMEM204. Integration of GWAS and eQTL effects demonstrated consistent regulatory shifts associated with PE-risk alleles, including downregulation of immune-related loci and upregulation of select vascular-associated genes. Long-read sequencing analyses identified 66 high-LD (r2 [≥] 0.80) SNP-SV-gene associations, including 12 replicated eQTL variants, 8 candidate SVs, and 3 replicated genes, suggesting that structurally complex genomic regions may contribute to the observed regulatory signals. ConclusionsThe tissues enriched in the regulatory signal highlight the importance of systemic endothelial biology in PE susceptibility. The findings of this study support a model in which PE-specific genetic susceptibility converges predominantly on interconnected immune and vascular regulatory mechanisms. The integration of eQTL analyses with long-read structural variant discovery provides additional insight into the complex genomic architecture underlying PE and highlights candidate regulatory loci that may not be adequately captured through conventional GWAS approaches alone. The study also emphasizes the importance of conducting functional genomic analyses in diverse populations to improve understanding of disease biology and advance precision medicine efforts. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/728031v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1caf4a5org.highwire.dtl.DTLVardef@1839b4eorg.highwire.dtl.DTLVardef@14922c3org.highwire.dtl.DTLVardef@894040_HPS_FORMAT_FIGEXP M_FIG C_FIG Regulatory Genomics of Preeclampsia-Specific Risk Variants Highlights Immune and Endothelial Mechanisms. GWAS summary statistics for preeclampsia, hypertension, SBP, and DBP were integrated to identify 10,843 preeclampsia-specific variants that were subsequently evaluated in cis-eQTL analyses using whole-blood RNA-sequencing data from 180 African American women (left). Cis-eQTL analyses identified 480 significant associations involving 277 variants and 192 genes (FDR [≤] 0.05), of which 69 eQTL-gene associations involving 35 variants and 14 genes replicated across five GTEx tissues, with strongest enrichment observed in vascular tissues, particularly artery tibial and artery aorta (center). Prioritized genes, including MICA, HLA-DPB1, SEMA4D, JUP, ZFP57, and TMEM204, converged on interconnected immune and endothelial pathways associated with systemic vascular dysfunction, impaired placentation, and inflammatory dysregulation in preeclampsia. Integration of long-read sequencing data further identified 66 high-LD SNP-SV-gene associations involving 12 replicated eQTL variants, 8 candidate structural variants, and 3 replicated genes, suggesting that structurally complex genomic regions may contribute to regulatory mechanisms not fully captured through conventional GWAS approaches alone. eQTL indicates expression quantitative trait locus; FDR, false discovery rate; GTEx, Genotype-Tissue Expression project; SBP, systolic blood pressure; DBP, diastolic blood pressure; LD, linkage disequilibrium; SV, structural variant.