Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity.

Area of Science:

• Genetics
• Nephrology
• Genomics

Background:

• Kidney function, measured by estimated glomerular filtration rate (eGFR), is crucial for defining chronic kidney disease (CKD).
• Genome-wide association studies (GWASs) have identified genetic loci associated with eGFR, but pinpointing causal variants and mechanisms remains challenging.

Purpose of the Study:

• To identify novel genetic loci associated with kidney function using large-scale GWAS data from diverse ancestries.
• To fine-map identified loci to pinpoint potential causal variants and elucidate molecular mechanisms underlying eGFR variation.
• To investigate the role of identified genes in kidney function and salt sensitivity.

Main Methods:

• Analysis of GWAS data from 71,638 individuals across four ancestries for estimated glomerular filtration rate (eGFR).
• Trans-ethnic fine-mapping of 20 genome-wide significant loci using linkage disequilibrium patterns.
• Enrichment analysis of credible variants for functional elements (e.g., DNase I hypersensitivity sites) in kidney cells.
• Expression quantitative trait loci (eQTL) analysis and functional studies in Drosophila and mouse models.

Main Results:

• Identified 20 loci significantly associated with kidney function (eGFR), with homogeneous allelic effects across ancestries.
• Fine-mapping identified credible variants enriched for kidney cell-specific DNase I hypersensitivity sites.
• Credible variants at the SLC34A1 locus were eQTLs for NFATC1 and RGS14.
• Loss-of-function mutations in Drosophila orthologs of NFATC1 and RGS14 affected salt stress sensitivity.
• Renal expression of Nfatc1 and Rgs14 was reduced in a salt-sensitive mouse model under high-salt diet or CKD conditions.

Conclusions:

• Trans-ethnic fine-mapping integrated with genomic annotation effectively defines molecular mechanisms of GWAS signals for kidney function.
• Salt sensitivity emerges as a potential marker for biological processes influencing kidney function and chronic kidney disease.
• NFATC1 and RGS14 are implicated as novel genes affecting kidney function, potentially through mechanisms related to salt sensitivity.