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.

Original publication

DOI

10.1016/j.ajhg.2016.07.012

Type

Journal article

Journal

American journal of human genetics

Publication Date

09/2016

Volume

99

Pages

636 - 646

Addresses

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

Keywords

SUMMIT Consortium, BioBank Japan Project, Kidney, Animals, Humans, Drosophila melanogaster, Diabetes Mellitus, Disease Models, Animal, Sodium Chloride, Deoxyribonuclease I, RGS Proteins, Glomerular Filtration Rate, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Alleles, Quantitative Trait Loci, Continental Population Groups, Ethnic Groups, Female, Male, Sodium-Phosphate Cotransporter Proteins, Type IIa, NFATC Transcription Factors, Renal Insufficiency, Chronic, Stress, Physiological, Salt-Tolerance, Genome-Wide Association Study