Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline

Abstract

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m²/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m² at follow-up among those with eGFRcrea 60 mL/min/1.73m² or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

Keywords: acute kidney injury; end-stage kidney disease; genome-wide association study; rapid eGFRcrea decline.

Figure 1 |. Illustration of the case-control definitions of Rapid3 and CKDi25.

Rapid3 defines cases as individuals with an eGFRcrea decline>3 mL/min/1.73m² per year and controls with an eGFRcrea decline between −1 and +1 mL/min/1.73m² per year. CKDi25 defines cases as a ≥25% drop from baseline eGFRcrea≥60 mL/min/1.73m² into eGFRcrea<60 mL/min/1.73m² at follow-up and controls as an eGFRcrea≥60 mL/min/1.73m² at baseline and follow-up. Shown are cases (red), controls (black) and excluded individuals (grey) according to the eGFRcrea values observed at baseline and follow-up.

Figure 2 |. Four loci identified with genome-wide significance for Rapid3 or CKDi25.

Shown are association P-values versus genomic position for Rapid3 (34,874 cases; 107,090 controls) and CKDi25 (19,901 cases; 175,244 controls). Horizontal dashed lines indicate genome-wide (5.00×10⁻⁸), Bonferroni-corrected (0.05/265≈1.89×10⁻⁴) and nominal (0.05) significance thresholds. The four identified genome-wide significant loci are annotated by the nearest genes (blue). The 264 loci reported previously for cross-sectional eGFRcrea are marked in orange and respective lead variants as red dots.