Abstract
We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10−8) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of “credible sets” of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans.
Highlights
Chronic kidney disease (CKD) is a major public health burden and affects nearly 10% of the global population.[1]
Lead SNPs were common across ancestry groups at all 20 loci, with each displaying modest effects on estimated glomerular filtration rate (eGFR) (Table S5)
These data are consistent with a single variant driving association signals in each locus; each variant is shared across ancestry groups and has homogeneous effects on eGFR in diverse populations
Summary
Chronic kidney disease (CKD) is a major public health burden and affects nearly 10% of the global population.[1] Reduced estimated glomerular filtration rate (eGFR), a measure of kidney function used to define CKD, is associated with premature cardiovascular disease and mortality, acute kidney injury, and progression to end stage renal disease (ESRD).[2] individuals of African and Hispanic descent suffer the largest burden of CKD,[3] the largest genome-wide association studies (GWASs) to search for kidney-function loci have been undertaken in populations of European and East Asian ancestry.[4,5,6,7,8] Many of these loci are characterized by common variant association signals that map to large genomic intervals, which contain many possible causal genes for eGFR, thereby limiting understanding of the downstream pathogenesis of CKD.
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