Genome-Wide Association Study of Creatinine Clearance Identifies New Loci for Kidney Function

IntroductionGenome-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. MethodsWe performed a GWA meta-analysis for creatinine clearance (CrCl), a muscle mass-independent kidney function phenotype, in 58,976 individuals of European descent from the Lifelines Cohort Study. ResultsWe identified 16 independent loci with 21 genome-wide 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 x 10-9) and rs117014836, located near the AGPAT4 gene (EAF = 0.02, P = 5.42 x 10-9). Both SNPs were also associated with eGFRcrea in Lifelines (rs146465192: P = 1.34 x 10-8; rs117014836: P = 3.64 x 10-7), but not in previously published eGFR GWASs. In silico follow-up analyses revealed that rs146465192 was associated with plasma IGF2R ({beta} = -0.519, P = 1.40 x 10-6), while rs117014836 was associated with blood expression levels of AGPAT4 (eQTL P = 6.54 x 10-6). Furthermore, we identified two female-specific CrCl loci (t-statistic P < 0.004): rs8002366 (GPC6) and rs12908437 (IGF1R), associated with GPC6 expression in kidney (eQTL P = 8.38 x 10-10) and IGF1R expression in blood (eQTL P = 2.62 x 10-6), respectively. ConclusionThis first large-scale GWAS of CrCl revealed two new genetic variants among both sexes and two female-specific variants influencing kidney function. Lay summaryKidney function is a complex phenotype influenced by many different factors, including genetics. Earlier genetic studies often used the creatinine-based estimated glomerular filtration rate (eGFRcrea) as the measure of kidney function. However, eGFRcrea is influenced not just by kidney function but also by an individuals muscle mass, which may distort the results. Therefore, in this study we used creatinine clearance (CrCl), a measure of kidney function independent of muscle mass, to look for genes in a European-ancestry population. We identified 16 genetic regions; two of which had not been found before. We also found two additional regions that were only related to CrCl in females. This shows the added value of investigating CrCl and suggests sex-based differences in how genetics affect kidney function.