Improved detection of genetic loci in estimated glomerular filtration rate and type 2 diabetes using a pleiotropic cFDR method

Abstract

Genome-wide association studies (GWAS) have been shown to have the potential of explaining more of the “missing heritability” of complex human phenotypes by improving statistical approaches. Here, we applied a genetic-pleiotropy-informed conditional false discovery rate (cFDR) to capture additional polygenic effects associated with estimated glomerular filtration rate (creatinine) (eGFRcrea) and type 2 diabetes (T2D). The cFDR analysis improves the identification of pleiotropic variants by incorporating potentially shared genetic mechanisms between two related traits. The Q–Q and fold-enrichment plots were used to assess the enrichment of SNPs associated with eGFRcrea or T2D, and Manhattan plots were used for showing chromosomal locations of the significant loci detected. By applying the cFDR method, we newly identified 74 loci for eGFRcrea and 3 loci for T2D with the cFDR criterion of 0.05 compared with previous related GWAS studies. Four shared SNPs were detected to be associated with both eGFRcrea and T2D at the significant conjunction cFDR level of 0.05, and these shared SNPs had not been reported in previous studies. In addition, we used DAVID analysis to perform functional analysis of the shared SNPs’ annotated genes and found their potential hidden associations with eGFRcrea and T2D. In this study, the cFDR method shows the feasibility to detect more genetic variants underlying the heritability of eGFRcrea and T2D, and the overlapping SNPs identified could be regarded as candidate loci that provide a thread of genetic mechanisms between eGFRcrea and T2D in future research.

The sodium/proton exchanger NHA2 regulates blood pressure through a WNK4-NCC dependent pathway in the kidney

“…We previously demonstrated that NHA2 resides in endosomes of β-cells and is critical for insulin secretion 10,11 . In support of this finding, a single-nucleotide polymorphism in the NHA2 gene was recently discovered in a genome-wide association study as a new locus associated with type 2 diabetes in humans 12 . In the rodent kidney, NHA2 was previously detected in the distal nephron, including the distal convoluted tubules (DCT), but its quantitative expression pattern along the nephron remains unknown 13,14 .…”

NHA2 promotes cyst development in an in vitro model of polycystic kidney disease

“…Second, a recent genome-wide association study (GWAS) of renal function identified NHA2 as a genetic risk locus for estimated glomerular filtration rate by serum creatinine. GFR, which shows heritability in the range of 36-75%, is commonly used to monitor kidney function decline in PKD (75). Third, NHA2 expression is predominant in the distal nephron where sodium reabsorption is under hormonal and dietary control and, consistent with the induction of renal NHA2 expression by a high salt diet in mouse (15,19).…”

NHA2 promotes cyst development in an in vitro model of polycystic kidney disease

“…Glomerular filtration rate, which shows heritability in the range of 36–75%, is commonly used to monitor kidney function decline in PKD (Schrier, ; Liu et al . ). Third, NHA2 expression is predominant in the distal nephron where sodium reabsorption is under hormonal and dietary control, consistent with the induction of renal NHA2 expression by a high salt diet in mouse (Fuster et al .…”