Genetic analysis of elevated levels of creatinine and cystatin C biomarkers reveals novel genetic loci associated with kidney function.

The rising prevalence of chronic kidney disease (CKD), affecting an estimated 37 million adults in the United States, presents a significant global health challenge. CKD is typically assessed using estimated Glomerular Filtration Rate (eGFR), which incorporates serum levels of biomarkers such as creatinine and cystatin C. However, these biomarkers do not directly measure kidney function; their elevation in CKD results from diminished glomerular filtration. Genome-wide association studies (GWAS) based on eGFR formulas using creatinine (eGFRcre) or cystatin C (eGFRcys) have identified distinct non-overlapping loci, raising questions about whether these loci govern kidney function or biomarker metabolism. In this study, we show that GWAS on creatinine and cystatin C levels in healthy individuals reveal both nonoverlapping genetic loci impacting their metabolism as well as overlapping genetic loci associated with kidney function; whereas GWAS on elevated levels of these biomarkers uncover novel loci primarily associated with kidney function in CKD patients.