Reduced estimated glomerular filtration rate (eGFR), the primary measure used to define CKD (eGFR<60 ml/min/1.73 m2) [4], is associated with an increased risk of cardiovascular morbidity and mortality [5], acute kidney injury [6], and end stage renal disease (ESRD) [6], [7]. Using genome-wide association studies (GWAS) in Tubacin clinical predominantly population-based cohorts, we and others have previously identified more than 20 genetic loci associated with eGFR and CKD [8]�C[11]. Although most of these genetic effects seem largely robust across strata of diabetes or hypertension status [9], evidence suggests that some of the loci such as the UMOD locus may have heterogeneous effects across these strata [11].

We thus hypothesized that GWAS in study populations stratified by four key CKD risk factors – age, sex, diabetes or hypertension status – may permit the identification of novel eGFR and CKD loci. We carried this out by extending our previous work [9] to a larger discovery sample of 74,354 individuals with independent replication in additional 56,246 individuals, resulting in a total of 130,600 individuals of European ancestry. To assess for potential heterogeneity, we performed separate genome-wide association analyses across strata of CKD risk factors, as well as in a more extreme CKD phenotype. Results Meta-analyses of GWAS on the 22 autosomes were performed for: 1) eGFR based on serum creatinine (eGFRcrea) and CKD (6,271 cases) in the overall sample, 2) eGFRcrea and CKD stratified by the four risk factors, and 3) CKD45, a more severe CKD phenotype defined as eGFRcrea <45 ml/min/1.

73 m2 in the overall sample (2,181 cases). For the stratified analyses, in addition to identifying loci that were significant within each stratum, we performed a genome-wide comparison of the effect estimates between strata of the four risk factors. A complete overview of the analysis workflow is given in Figure S1. All studies participating in the stage 1 discovery and stage 2 replication phases are listed in Tables S1 and S2. The characteristics of all stage 1 discovery samples by study are reported in Table S3, and information on study design and genotyping are reported in Table S4. Results of the eGFRcrea analyses are summarized in the Manhattan and quantile-quantile plots reported in Figures S2 and S3. A total of 21 SNPs from the discovery stage were carried forward for replication in an independent set of 56,246 individuals Anacetrapib (Tables S5 and S6).