Identification and Characterization of Genetic Risk Variants for Chronic Kidney Disease and Related Traits

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Chronic kidney disease (CKD) constitutes a serious public health burden of increasing prevalence and incidence worldwide. It can progress to end-stage renal disease and increases the risk for cardiovascular morbidity and mortality substantially. Despite strong evidence for a genetic component, few genetic susceptibility loci for CKD have been identified to date. Understanding the underpinnings of genetic susceptibility to kidney disease can provide valuable insights into important physiological pathways and disease mechanisms. The objective of this proposal is therefore to expand on previous work to discover and characterize novel common and rare genetic susceptibility variants for kidney dysfunction and CKD. This objective will be addressed by first conducting genome-wide association studies of CKD and measures of kidney function in ~45,000 individuals of European ancestry within a large international consortium. Discovery will be followed by targeted resequencing of the most promising genes in fewer individuals, including the UMOD gene we identified previously. Follow-up genotyping of risk variants and their characterization will be conducted in population-based and CKD-specific study samples. Finally, because exact measurement of the phenotype is essential for comprehensive variant identification, a novel CKD biomarker, serum FGF-23, will be measured in 3,000 participants of a population-based study. Associations of FGF-23 levels with CKD and its complications will be studied, and genetic and non-genetic correlates of FGF-23 and other components of the FGF-23 pathway will be identified. Combined, the proposed studies will provide novel insights into the genetics of chronic kidney disease.