Mapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program

Abstract

Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickle cell allele of betaglobin among non-Hispanic blacks. Our transcriptome-wide association study of kidney function in healthy kidney tissue identifies 36 previously unreported and nine known genes, and maps gene expression to renal cell types. In a Phenome-Wide Association Study in 192,868 MVP participants using a weighted genetic score we detect associations with CKD stages and complications and kidney stones. This investigation reinterprets the genetic architecture of kidney function to identify the gene, tissue, and anatomical context of renal homeostasis and the clinical consequences of dysregulation.

Fig. 1

Manhattan plot summarizing transethnic discovery meta-analysis of eGFR. The y axis shows the –log10 P-values and the x axis shows the chromosomal positions. The horizontal red line represents the thresholds of P-value = 5 × 10⁻⁸ for genome-wide significance. SNPs in red are in previously-identified kidney function loci, whereas SNPs in orange are in novel loci

Fig. 2

Juxtaposed mirror plots for S-PrediXcan and GWAS for eGFR. Log₁₀(p-values) for associations between genetically predicted gene expression (GPGE) analyses with eGFR in kidney tissue are juxtaposed with –log₁₀(p-values) from transethnic GWAS analyses (triangles represent odd numbered chromosomes, circles represent even numbered chromosomes). GWAS plot represents transethnic discovery meta-analysis results (chromosomes alternate by light gray and black coloration)

Fig. 3

Mapping eGFR-associated genes to kidney cell type clusters. Average expression level of GWAS/eQTL defined genes across overall transethnic (ALL), diabetic (DM), and non-diabetic (Non DM) analyses. Mean expression values of the genes were calculated in each cluster. Color scheme is based on z-score distribution. Each row represents one gene and each column is single cell type cluster (as defined by Park et al.) on the heatmap. Endo: endothelial, vascular, descending loop of Henle, Podo: podocyte, PT: proximal tubule, LOH: ascending loop of Henle, DCT: distal convoluted tubule, CD-PC: collecting duct principal cell, CD-IC: CD intercalated cell, Fib: fibroblast, Macro: macrophage, Neutro: neutrophil, NK: natural killer cell