Genetic Association for Renal Traits among Participants of African Ancestry Reveals New Loci for Renal Function

Abstract

Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m2), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10−7) and FNDC1 (p-value = 3.0×10−7) for UACR, and KCNQ1 with eGFR (p = 3.6×10−6). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.

Identification of chromosome 3q28 andALPK1as susceptibility loci for chronic kidney disease in Japanese individuals by a genome-wide association study

“…Although recent genome-wide association studies (GWASs) have implicated several loci and genes in renal function or predisposition to CKD or ESRD in Caucasian7–11 or African American12 13 populations, or in renal function related traits in East Asian populations,14 the genes that contribute to genetic susceptibility to CKD in Japanese individuals remain to be identified definitively.…”

Genetics and Chronic Kidney Disease

“…Consistent results in African and European ancestry populations is reassuring and smaller haplotype blocks in those of African ancestry may facilitate detection of causal SNPs. 106 Perhaps surprisingly, although several major eGFRassociated loci were found to be associated with development of CKD (e.g. UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1), only UMOD was nominally associated with ESRD.…”

Activators of G Protein Signaling in the Kidney

“…A recent genome-wide association study suggested a potential link between AGS8/FNDC1 and urinary albumin-tocreatinine ratio in African Americans from the CARe Renal Consortium (Liu et al, 2011). However, morpholino knockdown of AGS8/FNDC1 in zebrafish did not support a role for this protein during renal development or dysfunction (Liu et al, 2011).…”