Multiple loci associated with indices of renal function and chronic kidney disease

Abstract

Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m(2)) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 × 10(-8)) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.

Figure 1. Meta-analysis -log₁₀(P-value) vs. genomic position plots for CKD (A), eGFRcrea (B), and eGFRcys (C) in the discovery samples

Genomic loci with evidence of suggestive association (p<4*10⁻⁷) are plotted in orange and with significant association (p<5*10⁻⁸) in red, with the exception of the SNP at the JAG1 locus on chromosome 20 (panel B, grey) which did not replicate.

Figure 2. Genetic architecture of the genome-wide significant susceptibility loci for renal disease in the discovery samples: (A): UMOD gene region, (B): SHROOM3 gene region, (C): GATM/SPATA5L1 gene region, (D) CST genes region, (E) STC1 gene region

−log10 P-values are plotted versus genomic position (Build 36). The most significant SNP in each region is plotted in blue. LD based on the HapMap CEU sample is color-coded: red (r² to top SNP 0.8–.0), orange (0.5–.8), yellow (0.2–.5), and white (<0.2). Gene annotations are based on Build 36 and arrows present direction of transcription. P-values are obtained from the discovery traits: CKD (UMOD), eGFRcrea (SHROOM3, GATM), eGFRcys (CST, STC1).

Figure 3. Meta-analysis of the odds of CKD per each additional copy of the minor T allele at UMOD rs12917707 across strata of major kidney disease risk factors

Error bars correspond to 95% confidence intervals. Meta-analysis values obtained from the discovery samples.