Heritability of End-Stage Renal Disease: A Swedish Adoption Study

Akrawi, Delshad Saleh; PirouziFard, Mir Nabi; Fjellstedt, Erik; Sundquist, Jan; Sundquist, Kristina; Zöller, Bengt

doi:10.1159/000484327

Cited by 9 publications

(9 citation statements)

References 40 publications

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“…This was true not only for diseases with established high heritability but also entities, such as AKI, whose genetic basis is less pronounced 1 – 4 , 55 However, as reflected in our plot comparing AUCs using different sets of predictors, as one includes more measurable clinical risk factors for prediction, the incremental contribution of the PRS was smaller. In particular, much of the genetic risk was mediated through eGFR.…”

Section: Discussionmentioning

confidence: 78%

Polygenic Risk Scores for Kidney Function and Their Associations with Circulating Proteome, and Incident Kidney Diseases

Jin

Tin

et al. 2021

JASN

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Background: Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (estimated glomerular filtration rate, eGFR). The relationship of polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known. Methods: We developed a genome-wide polygenic risk score (PRS) for eGFR by applying the LDpred algorithm to summary statistics generated from a multiethnic meta-analysis of CKDGen Consortium GWAS (N=765,348) and UK Biobank GWAS (90% of the cohort; N=451,508), followed by best parameter selection using the remaining 10% of UK Biobank (N=45,158). We then tested the association of the PRS in the Atherosclerosis Risk in Communities (ARIC) study (N=8,866) with incident chronic kidney disease, kidney failure, and acute kidney injury. We also examined associations between the PRS and 4,877 plasma proteins measured at at middle age and older adulthood and evaluated mediation of PRS associations by eGFR. Results: The developed PRS showed significant associations with all outcomes with hazard ratios (95% CI) per 1 SD lower PRS ranged from 1.06 (1.01, 1.11) to 1.33 (1.28, 1.37). The PRS was significantly associated with 132 proteins at both time points. The strongest associations were with cystatin-C, collagen alpha-1(XV) chain, and desmocollin-2. Most proteins were higher at lower kidney function, except for 5 proteins including testican-2. Most correlations of the genetic PRS with proteins were mediated by eGFR. Conclusions: A PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases and broadly influences the plasma proteome, primarily mediated by eGFR.

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Section: Discussionmentioning

confidence: 78%

Polygenic Risk Scores for Kidney Function and Their Associations with Circulating Proteome, and Incident Kidney Diseases

Jin

Tin

et al. 2021

JASN

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“…Our results demonstrate that, for a spectrum of kidney diseases, not only diseases with established high heritability, but also entities like AKI whose genetic basis is less pronounced, [1][2][3][4]22 PRS can now identify individuals with higher genetic risk for over 30 years of follow up, suggesting a potential role in further research and clinical medicine.…”

Section: Plasma Proteome As An Intermediate Traitmentioning

confidence: 90%

“…The heritability estimated by family studies are 30-75%. [1][2][3][4] Genomewide associations studies (GWAS) have grown rapidly in the last decade and identified numerous loci for kidney function, which gave rise to increasing attention to testing polygenic risk scores (PRS) as risk factors for kidney diseases risks. [5][6][7][8][9][10][11] However, previous PRS provided limited risk stratification for adverse kidney outcomes such as end-stage kidney disease (ESKD).…”

Section: Intruductionmentioning

confidence: 99%

“…Using large studies and new algorithms, we investigated the strength of associations of PRS for kidney function with incident kidney diseases over 30 years of follow-up in a deeply phenotyped community-based cohort. We included diseases strongly related to kidney function with evidence of a strong genetic basis, including chronic kidney disease (CKD), end-stage kidney disease (ESKD), and kidney failure, [1][2][3][4] as well as acute kidney injury (AKI). 22 We also examined 4,877 plasma proteins measured at two time points approximately 20 years apart in relation to both genetic susceptibility to low kidney function and the concurrent kidney function itself, in order to evaluate the strengths of proteomic associations with genetically predicted risk and physiological changes and how those associations change over time.…”

Section: Intruductionmentioning

confidence: 99%

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Polygenic Risk Scores for Kidney Function to the Circulating Proteome, and Incident Kidney Diseases: the Atherosclerosis Risk in Communities Study

Jin

Tin

et al. 2020

Preprint

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Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (estimated glomerular filtration rate, eGFR). The relationship of polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known. We developed a genome-wide polygenic risk score (PRS) using a weighted average of 1.2 million SNPs for eGFR using the LDpred algorithm, summary statistics generated by a European-ancestry (EA) meta-analysis of the CKDGen Consortium (N=558,423) and UK Biobank GWAS for eGFR (90% of the cohort; N=289,432), followed by best parameter selection using data from the remaining 10% of the UK Biobank (N=32,159). We then tested the association of the PRS among 8,886 EA participants in the Atherosclerosis Risk in Communities (ARIC) study (mean age: 54±6 years, 53% female) with incident chronic kidney disease (CKD), end stage kidney disease (ESKD), kidney failure (KF), and acute kidney injury (AKI). We also examined 4,877 plasma proteins measured at two time points (visit 3 (1993-95) and visit 5 (2011-13)) in relation to the PRS and compared associations between the proteome and eGFR itself. All models were adjusted for age, sex, center, and the first 10 principal components of ancestry. The developed PRS had an R2 for eGFR of 0.07 in ARIC. Over 30 years of follow up, the number of incident CKD, ESKD, KF, and AKI were 2,959, 137, 470, and 1,723, respectively. The PRS showed significant associations with all outcomes: hazard ratios (95% CI) per 1 SD lower PRS were 1.33 (1.28, 1.39), 1.20 (1.00, 1.42), 1.17 (1.06, 1.28), and 1.07 (1.02, 1.12) for incident CKD, ESKD, KF, and AKI respectively. The PRS was significantly associated (Bonferroni threshold P<1.02 × 10−5) with 108 proteins at both time points. The strongest associations were with cystatin-C (a marker of kidney function used in clinical practice), collagen alpha-1 (XV) chain, and desmocollin-2. All significant correlations with the PRS were negative, except those of testican-2 and angiostatin. Correlations of proteins with eGFR were much stronger than those with the PRS. Overall, we demonstrated that the PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases as well as broadly influence the plasma proteome.

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“…A family history of kidney disease is reported by 20–34% of adults with chronic kidney disease (CKD) [1-4]. Familial clustering of CKD, notably among patients with end-stage renal disease (ESRD), is well documented and largely attributed to genetic causes [3, 5-8] that may be under-recognized in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Family History is Important to Identify Patients with Monogenic Causes of Adult-Onset Chronic Kidney Disease

Granhøj

Tougaard

Lildballe

et al. 2021

Nephron

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Monogenic causes of chronic kidney disease (CKD) are more prevalent in adults than previously thought, as causative gene variants are found in almost 10% of unselected patients with CKD. Even so, genetic testing in patients with adult-onset CKD is uncommon in clinical practice and the optimal criteria for patient selection remain unclear. A family history of kidney disease emerges as one marker associated with a high diagnostic yield of genetic testing. We present 3 cases of adult-onset CKD with underlying monogenic causes exemplifying different modes of inheritance. Case 1 is a 60-year-old male with slowly progressive CKD initially ascribed to hypertension and diabetes despite a family history with several affected first-degree relatives. A pathogenic MUC1 variant was found, and thus we identified the first Danish family of MUC1-associated autosomal dominant tubulointerstitial kidney disease. Case 2 is a 40-year-old female with nephrocalcinosis, nephrolithiasis, and unexplainable hypercalcemia consistent with vitamin D intoxication. The family history indicated autosomal recessive inheritance, and genetic testing revealed 2 pathogenic CYP24A1 variants in compound heterozygous form associated with idiopathic infantile hypercalcemia. Case 3 is a 50-year-old male with microscopic hematuria, proteinuria, and hearing loss. Electron microscopy of renal biopsy showed thin basal membrane syndrome, and the family history indicated X-linked inheritance. A novel missense variant in COL4A5 was identified, suggesting an atypical late-onset form of X-linked Alport syndrome. This case series illustrates the heterogeneous presentations of monogenic kidney disease in adults and emphasizes the importance of family history for initiating genetic testing to identify underlying monogenic causation. Moreover, we discuss the potential impact of genetic diagnostics on patient management and genetic family counseling.

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Heritability of End-Stage Renal Disease: A Swedish Adoption Study

Cited by 9 publications

References 40 publications

Polygenic Risk Scores for Kidney Function and Their Associations with Circulating Proteome, and Incident Kidney Diseases

Polygenic Risk Scores for Kidney Function and Their Associations with Circulating Proteome, and Incident Kidney Diseases

Polygenic Risk Scores for Kidney Function to the Circulating Proteome, and Incident Kidney Diseases: the Atherosclerosis Risk in Communities Study

Family History is Important to Identify Patients with Monogenic Causes of Adult-Onset Chronic Kidney Disease

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