Genome-Wide Association Study on Creatinine Clearance in the Lifelines Cohort Study

Background: Genome-wide association studies (GWAS) for kidney function have mainly focused on creatinine-based glomerular filtration rate (eGFR). However, variation in muscle mass reduces the accuracy of the eGFR. Creatinine clearance is able to assess kidney function independently of muscle mass. Our aim was to identify genes influencing creatinine clearance as an alternative phenotype of kidney function. In addition, we aimed to analyse overlap of creatinine clearance loci with eGFR loci. Methods: We performed a GWAS on creatinine clearance and eGFR (creatinine-based CKD-EPI 2009) in 58,976 individuals of European descent from the Lifelines Cohort Study. Genetic correlation between phenotypes and heritability was estimated using linkage disequilibrium score regression. In addition, we performed expression Quantitative Trait Loci (eQTL) analyses. Results: We identified 16 independent loci for creatinine clearance with 21 genome-wide significant lead single nucleotide polymorphism (SNPs) (P < 5x10−8). In addition, we found 65 loci for eGFR with 95 lead SNPs. Two new SNPs, not previously related to eGFR in CKDGen were discovered (rs146465192: EAF = 0.01, P = 3.38x10−09; rs117014836: EAF = 0.02, P = 5.42x10−09). Both SNPs were also associated with eGFR (rs146465192: P = 1.34x10−08; rs117014836: P = 3.64x10−07) in our analysis. The variant rs117014836 was associated with expression levels of AGPAT4 gene in blood (eQTL P = 6.54x10-6). The common SNP heritability of creatinine clearance was 12%. We observed a high genetic correlation between creatinine clearance and eGFR (rg = 0.77). Conclusion: We found two new SNPs, one of which influenced blood expression of AGPAT4 gene,which plays a crucial role in modulating the diversity of fatty acid chains. This supports the role of lysophospholipid metabolism in impaired kidney function.