Abstract: TH-PO0037
Genome-Wide (GWAS) and Phenome-Wide Association Study (PheWAS) Identifies DACH1 as a Novel Candidate Regulator of Potassium Homeostasis
Session Information
- Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Fluid, Electrolytes, and Acid-Base Disorders
- 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic
Authors
- Boufford, Camille Klimas, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
- Subramanya, Arohan R., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
Background
Unlike a traditional GWAS, which interrogates genetic variation for a single trait, genome-wide PheWAS characterizes fine-mapped genetic associations across the entire phenome. We reasoned that integrating PheWAS with existing multiomics datasets could identify novel distal nephron (DN) expressed gene networks involved in human renal potassium (K+) homeostasis.
Methods
Using PheWAS/GWAS summary data from VA’s Million Veteran Program (MVP), the UK Biobank, and the NHGRI-EBI GWAS Catalog, we identified single nucleotide variants (SNVs) associated with blood potassium concentration at genome-wide significance (p<5x10-8). We then selected K+ associated SNVs that mapped to DN-expressed genes, as determined by RNA-seq data (NHLBI ESBL, Kidney Cell Explorer) and the Human Protein Atlas. The VA’s Centralized Phenomics Resource (CIPHER) and the UCSC Genome Browser were used to fine-map SNVs to specific genetic loci and retain mapped genes with variant-associated Phecodes enriched for canonical DN K+ response traits. Top candidates were preliminarily tested for K+ sensitivity via immunofluorescent staining (IF) of wild-type C57BLJ/6 mouse kidney tissue after exposure to various K+ diets for 10 days.
Results
We identified 377 statistically significant potassium-associated genes potentially involved in renal K+ handling. Multiomics analysis narrowed this list to 6 DN-expressed candidates, five of which are known potassium regulators (SLC12A3, KLHL3, WNK1, SCNN1B, and CAB39). The sixth, DACH1 (intronic SNV rs626277), encodes a transcription factor that suppresses cell cycle progression. IF staining in potassium-replete mice on control diet revealed renal tubule Dach1 expression that was restricted to DN nuclei. Dietary K+ excess increased the expression of Dach1 in DN nuclei relative to control K+. In contrast, K+ deprivation decreased nuclear DN-Dach1 expression and redistributed the protein to cytosolic WNK bodies, specialized condensates that coordinate the kidney’s response to hypokalemic stress.
Conclusion
Integrating population genetics with tissue-specific multiomics, we identified DACH1 as a novel DN-specific potassium-sensitive gene, potentially linking the cell cycle to K+ homeostasis via distal tubule remodeling. More broadly, these findings highlight public PheWAS data as an effective hypothesis-generating tool for gene discovery and mechanistic insight.
Funding
- NIDDK Support