Genome-wide association study of creatinine clearance identifies new loci for kidney function

Abstract

Introduction: Genome-wide association studies (GWAS) for kidney function have mainly focused on creatinine-based glomerular filtration rate (eGFRcrea), which is affected by variation in muscle mass. Moreover, the genetic basis of the sexual dimorphism of chronic kidney disease is underexplored. Methods: We performed a GWAS meta-analysis for creatinine clearance (CrCl), a muscle mass-independent measure of kidney function, in 58,976 individuals of European ancestry from the Lifelines Cohort Study, including sex-specific analyses. Results: We identified 16 independent loci with 21 genomewide significant lead single-nucleotide polymorphisms (SNPs) associated with CrCl, two of which had not been reported previously in kidney function GWASs: rs146465192, located near the RP1-249F5.3 gene (effect allele frequency (EAF) 0.01, P = 3.38 & times; 10-9 ) and rs117014836, located near the AGPAT4 gene (EAF 0.02, P = 5.42 & times; 10-9 ). Both loci were also significantly associated with eGFRcrea in Lifelines, but not in previously published eGFR GWASs. In silico annotations revealed that rs146465192 was associated with plasma levels of IGF2R protein, whereas rs117014836 was associated with blood expression of AGPAT4 transcript. Furthermore, we identified two significant female-specific CrCl loci: rs8002366 (GPC6 locus) and rs12908437 (IGF1R locus), associated with GPC6 expression in kidney and IGF1R expression in blood, respectively. Conclusions: Our first large-scale GWAS of CrCl revealed two new genetic variants among both sexes and two female-specific variants influencing kidney function and highlighting the value of CrCl as a muscle mass-independent phenotype.