Key result
Genetically predicted elevated systolic blood pressure increases chronic kidney disease risk via renal vascular mechanisms.
Why the study?
Hypertension and chronic kidney disease frequently co-occur, but the shared genetic mechanisms underlying this relationship remain incompletely understood.
Observational (n=1,761,641)
Effect estimate: β = 0.035
p-value: p=3.4 × 10⁻¹⁰
This multi-omics study provides robust genetic evidence that elevated blood pressure causally increases chronic kidney disease risk and identifies shared therapeutic targets like FGF5, CPS1, and UMOD for dual cardiorenal protection.
Supports causal SBP-CKD link via renal/vascular pathways; leaves open whether targeting shared genes alters outcomes in trials.
Hypertension and chronic kidney disease (CKD) are frequently comorbid, yet their shared genetic mechanisms remain incompletely understood. We performed a systematic multi-omics integration utilizing GWAS summary statistics (> 1.7 million individuals). Key analytical approaches and their primary findings were: (1) LD Score Regression identified significant genetic correlations (SBP-CKD: rg = 0.206, P = 4.1 × 10⁻¹⁰); (2) Bayesian colocalization (coloc/HyPrColoc) prioritized 114 shared causal variants (H4 > 0.8); (3) Transcriptome-wide association (TWAS) confirmed gene expression associations in kidney and vascular tissues; (4) Bidirectional Mendelian randomization established a causal effect of BP on CKD risk (IVW P = 3.4 × 10⁻¹⁰) with sensitivity analyses (Cochran Q, MR-Egger, leave-one-out); (5) Single-cell enrichment implicated renal tubular and vascular smooth muscle cells; (6) PheWAS evaluated pleiotropy and safety profiles of priority drug targets. We identified 434 shared BP-kidney genes, including 36 multi-trait genes associated with all four phenotypes (SBP, DBP, eGFR, CKD). The top prioritized genes (FGF5, CPS1, UMOD, SHROOM3) were supported by convergent evidence from MAGMA, TWAS, and colocalization (HyPrColoc PP = 1.00 for FGF5 and CPS1). Forward MR confirmed a causal effect of elevated SBP on CKD risk (IVW β = 0.035 per mmHg, P = 3.4 × 10⁻¹⁰), while reverse MR showed no robust evidence for reverse causation after accounting for pleiotropy (Egger intercept P = 0.001). Cell-type enrichment implicated renal tubular cells (proximal, distal, collecting duct) and vascular smooth muscle cells. Transcription factor enrichment identified HNF1A, HNF4A, and MEF2C as computationally enriched candidates. Cross-ancestry validation in East Asian populations (N ≈ 145,000) showed directionally consistent effects, although with reduced statistical power. PheWAS revealed potential pleiotropic effects for FGF5 and UMOD, informing drug safety considerations. This study constructs a genetic atlas of the “renal-vascular” axis linking systemic pressure to local renal injury, prioritizing molecular targets for precision therapeutic strategies in cardiorenal medicine.
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Song et al. (2026) conducted an observational in Hypertension and Chronic Kidney Disease (n=1,761,641). Genetically predicted elevated systolic blood pressure vs. Lower genetically predicted systolic blood pressure was evaluated on Causal effect of elevated systolic blood pressure on chronic kidney disease risk (β = 0.035, p=3.4 × 10⁻¹⁰). Genetically predicted elevated systolic blood pressure causally increased the risk of chronic kidney disease (IVW β = 0.035 per mmHg, P = 3.4 × 10⁻¹⁰), with shared genetic architecture implicating renal tubular and vascular smooth muscle cells.
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