scholarly journals Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals

2020 ◽  
Author(s):  
Kira J Stanzick ◽  
Yong Li ◽  
Mathias Gorski ◽  
Matthias Wuttke ◽  
Cristian Pattaro ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Kidney Function ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Estimated Gfr ◽  
Genome Wide ◽  
Credible Sets ◽  
Gene Prioritisation ◽  
Variance Explained

ABSTRACTChronic kidney disease (CKD) has a complex genetic underpinning. Genome-wide association studies (GWAS) of CKD-defining glomerular filtration rate (GFR) have identified hundreds of loci, but prioritization of variants and genes is challenging. To expand and refine GWAS discovery, we meta-analyzed GWAS data for creatinine-based estimated GFR (eGFRcrea) from the Chronic Kidney Disease Genetics Consortium (CKDGen, n=765,348, trans-ethnic) and UK Biobank (UKB, n=436,581, Europeans). The results (i) extend the number of eGFRcrea loci (424 loci; 201 novel; 8.9% eGFRcrea variance explained by 634 independent signals); (ii) improve fine-mapping resolution (138 99% credible sets with ≤5 variants, 44 single-variant sets); (iii) ascertain likely kidney function relevance for 343 loci (consistent association with alternative biomarkers); and (iv) highlight 34 genes with strong evidence by a systematic Gene PrioritiSation (GPS). We provide a sortable, searchable and customizable GPS tool to navigate through the in silico functional evidence and select relevant targets for functional investigations.

scholarly journals Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kira J. Stanzick ◽  
Yong Li ◽  
Pascal Schlosser ◽  
Mathias Gorski ◽  
Matthias Wuttke ◽  
...  
Keyword(s):  
Kidney Function ◽  
Fine Mapping ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Functional Studies ◽  
Genome Wide ◽  
Credible Sets ◽  
Variance Explained

AbstractGenes underneath signals from genome-wide association studies (GWAS) for kidney function are promising targets for functional studies, but prioritizing variants and genes is challenging. By GWAS meta-analysis for creatinine-based estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics Consortium and UK Biobank (n = 1,201,909), we expand the number of eGFRcrea loci (424 loci, 201 novel; 9.8% eGFRcrea variance explained by 634 independent signal variants). Our increased sample size in fine-mapping (n = 1,004,040, European) more than doubles the number of signals with resolved fine-mapping (99% credible sets down to 1 variant for 44 signals, ≤5 variants for 138 signals). Cystatin-based eGFR and/or blood urea nitrogen association support 348 loci (n = 460,826 and 852,678, respectively). Our customizable tool for Gene PrioritiSation reveals 23 compelling genes including mechanistic insights and enables navigation through genes and variants likely relevant for kidney function in human to help select targets for experimental follow-up.

scholarly journals Multi-phenotype genome-wide association studies of the Norfolk Island isolate implicate pleiotropic loci involved in chronic kidney disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ngan K. Tran ◽  
Rodney A. Lea ◽  
Samuel Holland ◽  
Quan Nguyen ◽  
Arti M. Raghubar ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Kidney Function ◽  
Principal Components ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Functional Variants ◽  
Genome Wide ◽  
Norfolk Island

AbstractChronic kidney disease (CKD) is a persistent impairment of kidney function. Genome-wide association studies (GWAS) have revealed multiple genetic loci associated with CKD susceptibility but the complete genetic basis is not yet clear. Since CKD shares risk factors with cardiovascular diseases and diabetes, there may be pleiotropic loci at play but may go undetected when using single phenotype GWAS. Here, we used multi-phenotype GWAS in the Norfolk Island isolate (n = 380) to identify new loci associated with CKD. We performed a principal components analysis on different combinations of 29 quantitative traits to extract principal components (PCs) representative of multiple correlated phenotypes. GWAS of a PC derived from glomerular filtration rate, serum creatinine, and serum urea identified a suggestive peak (pmin = 1.67 × 10–7) that mapped to KCNIP4. Inclusion of other secondary CKD measurements with these three kidney function traits identified the KCNIP4 locus with GWAS significance (pmin = 1.59 × 10–9). Finally, we identified a group of two SNPs with increased minor allele frequencies as potential functional variants. With the use of genetic isolate and the PCA-based multi-phenotype GWAS approach, we have revealed a potential pleotropic effect locus for CKD. Further studies are required to assess functional relevance of this locus.

scholarly journals Shroom3, a gene associated with chronic kidney disease, modulates epithelial recovery after acute kidney injury

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0003802021
Author(s):  
Aihua Li ◽  
Joanna Cunanan ◽  
Hadiseh Khalili ◽  
Timothy Plageman ◽  
Kjetil Ask ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Kidney Function ◽  
Genetic Variants ◽  
Association Studies ◽  
Kidney Injury ◽  
Tubular Damage ◽  
Genome Wide Association Studies ◽  
Cellular Mechanisms

Background: Ischemia induced acute kidney injury (AKI) resulting in tubular damage can often progress to chronic kidney disease (CKD) and is a common cause of nephrology consultation. Following renal tubular epithelial damage, molecular and cellular mechanisms are activated to repair and regenerate the damaged epithelium. If these mechanisms are impaired, AKI can progress to CKD. Even in patients whose kidney function returns to normal baseline are more likely to develop CKD. Genome-wide association studies have provided robust evidence that genetic variants in SHROOM3, which encodes an actin-associated protein, are associated with CKD and poor outcomes in transplanted kidneys. Here, we sought to further understand the associations of Shroom3 in CKD. Methods: Kidney ischemia was induced in wild-type and Shroom3 heterozygous null mice (Shroom3Gt/+) and the mechanisms of cellular recovery and repair were examined. Results: A 28-minute bilateral ischemia in Shroom3Gt/+ mice resulted in 100% mortality within 24 hours. After 22-minute ischemic injury, Shroom3Gt/+ mice had a 16% increased mortality, worsened kidney function, and significantly worse histopathology, apoptosis, proliferation, inflammation, and fibrosis after injury. The cortical tubular damage in Shroom3Gt/+ was associated with disrupted epithelial redifferentiation, disrupted Rho-kinase/myosin signaling, and disorganized apical F-actin. Analysis of Madin Darby Canine Kidney Cells showed the levels of Shroom3 are directly correlated to apical organization of actin and actomyosin regulators. Conclusion: These findings establish that Shroom3 is required for epithelial repair and redifferentiation through the organization of actomyosin regulators and could explain why genetic variants in Shroom3 are associated with CKD and allograft rejection.

scholarly journals Polymorphism in the GATM Locus Associated with Dialysis-Independent Chronic Kidney Disease but Not Dialysis-Dependent Kidney Failure

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 834
Author(s):  
Špela Šalamon ◽  
Sebastjan Bevc ◽  
Robert Ekart ◽  
Radovan Hojs ◽  
Uroš Potočnik
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Kidney Failure ◽  
Association Studies ◽  
Genetic Difference ◽  
Genome Wide Association Studies ◽  
Healthy Controls ◽  
Genome Wide ◽  
Stage Renal Disease ◽  
End Stage

The ten most statistically significant estimated glomerular filtration rate (eGFRcrea)-associated loci from genome-wide association studies (GWAs) are tested for associations with chronic kidney disease (CKD) in 208 patients, including dialysis-independent CKD and dialysis-dependent end-stage renal disease (kidney failure). The allele A of intergenic SNP rs2453533 (near GATM) is more frequent in dialysis-independent CKD patients (n = 135, adjusted p = 0.020) but not dialysis-dependent kidney failure patients (n = 73) compared to healthy controls (n = 309). The allele C of intronic SNP rs4293393 (UMOD) is more frequent in healthy controls (adjusted p = 0.042) than in CKD patients. The Allele T of intronic SNP rs9895661 (BCAS3) is associated with decreased eGFRcys (adjusted p = 0.001) and eGFRcrea (adjusted p = 0.017). Our results provide further evidence of a genetic difference between dialysis-dialysis-independent CKD and dialysis-dependent kidney failure, and add the GATM gene locus to the list of loci associated only with dialysis-independent CKD. GATM risk allele carriers in the dialysis-independent group may have a genetic susceptibility to higher creatinine production rather than increased serum creatinine due to kidney malfunction, and therefore, do not progress to dialysis-dependent kidney failure. When using eGFRcrea for CKD diagnosis, physicians might benefit from information about creatinine-increasing loci.

scholarly journals Genome-wide association studies in pediatric chronic kidney disease

2015 ◽  
Vol 31 (8) ◽  
pp. 1241-1252 ◽  
Author(s):  
Jayanta Gupta ◽  
Peter A. Kanetsky ◽  
Matthias Wuttke ◽  
Anna Köttgen ◽  
Franz Schaefer ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

scholarly journals Emerging Insights Into Chronic Renal Disease Pathogenesis in Hypertension From Human and Animal Genomic Studies

Hypertension ◽  
2021 ◽  
Vol 78 (6) ◽  
pp. 1689-1700
Author(s):  
Isha S. Dhande ◽  
Michael C. Braun ◽  
Peter A. Doris
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Chronic Renal Disease ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Renal Vasculature ◽  
Adaptive Immune ◽  
Genome Wide ◽  
Genomic Studies ◽  
Emerging Themes

The pathogenic links between elevated blood pressure and chronic kidney disease remain obscure. This article examines progress in population genetics and in animal models of hypertension and chronic kidney disease. It also provides a critique of the application of genome-wide association studies to understanding the heritability of renal function. Emerging themes identified indicate that heritable risk of chronic kidney disease in hypertension can arise from genetic variation in (1) glomerular and tubular protein handling mechanisms; (2) autoregulatory capacity of the renal vasculature; and (3) innate and adaptive immune mechanisms. Increased prevalence of hypertension-associated chronic kidney disease that occurs with aging may reflect amplification of heritable risks by normal aging processes affecting immunity and autoregulation.

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