Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen

Abstract

Background: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.

Methods: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.

Results: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1).

Conclusions: The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

Keywords: diabetes; diabetic nephropathy; end-stage renal disease; genetic renal disease; human genetics; kidney disease.

Graphical abstract

Figure 1.

Phenotypic analysis of DKD. Schematic diagram of outcomes analyzed in this study. Numbers indicate the total number of cases (darker gray) and controls (lighter gray) included in the meta-analyses for each phenotype. ESKD defined as eGFR<15 ml/min per 1.73 m² or undergoing dialysis or having renal transplant.

Figure 2.

Genome-wide association testing of all ten phenotypic comparisons. Multiphenotype Manhattan plot shows lowest P value at each marker for each of the ten phenotypic comparisons, under the standard and fully-adjusted model. Significance of SNPs (−log₁₀[P value], y axis) is plotted against genomic location (x axis). Loci surpassing genome-wide significance (red line) and/or study-wide significance (blue line) are colored by phenotype.

Figure 3.

Adjusted residuals of GBM width by rs55703767 genotype and sex. Box and whisker plot of residuals of mean GBM width after adjusting for age, sex, and diabetes duration, stratified by GG, GT, or TT genotype at rs55703767, with overlay of individual data points for both women (pink) and men (blue).

Figure 4.

Association at rs55703767 (COL4A3) stratified by HbA1c below or above 7.5%, for the phenotypes reaching genome-wide significance in the combined meta-analysis. Analysis included 1344 individuals with time-weighted mean HbA1c <7.5% (58 mmol/mol), and 2977 with mean HbA1c ≥7.5% from the FinnDiane study; the individuals had median 19 HbA1c measurements (range 1–129).

Figure 5.

Single-cell RNA-sequencing in mouse kidney shows COL4A3, SNCAIP, and BMP7 are specifically expressed in podocytes. Mean expression values of the genes were calculated in each cluster. The color scheme is on the basis of z-score distribution; the map shows genes with z-score >2. In the heatmap, each row represents one gene and each column is a single cell type. Percentages of assigned cell types are summarized in the right panel. CD-IC, collecting duct intercalated cell; CD-PC, collecting duct principal cell; CD-Trans, collecting duct transitional cell; DCT, distal convoluted tubule; Endo, containing endothelial, vascular, and descending loop of Henle; Fib, fibroblast; LOH, ascending loop of Henle; Lymph, lymphocyte; Macro, macrophage; Neutro, neutrophil; NK, natural killer cell; Podo, podocyte; PT, proximal tubule.