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

Tran, Kim Ngan; Lea, Rodney Arthur; Holland, Samuel; Nguyen, Quan; Raghubar, Arti M.; Sutherland, Heidi G.; Benton, Miles C.; Haupt, Larisa M.; Blackburn, Nicholas B.; Curran, Joanne E.; Blangero, John; Mallett, Andrew; Griffiths, Lyn R.

doi:10.1038/s41598-021-98935-4

Cited by 3 publications

(3 citation statements)

References 45 publications

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“…7 Previously, we employed principal component analysis (PCA) on multiple quantitative phenotypes associated with CKD, uncovering a novel susceptibility gene for kidney function that remained undetected in single-phenotype GWASs. 8 In this study, we introduce and implement a new approach termed combinatorial PCA to further investigate the genetic basis of CKD within the UK Biobank dataset. As a result, we identified a new locus, SH2B3 (SH2B adaptor protein 3), to be associated with CKD.…”

Section: Introductionmentioning

confidence: 99%

A multi-phenotype approach implicatesSH2B3in the genetics of chronic kidney disease

Tran,

Sutherland,

Mallett

et al. 2024

Preprint

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Chronic kidney disease (CKD) is a complex condition with diverse underlying causes that lead to a progressive decline in kidney function. Genome-wide association studies (GWASs) have identified numerous genetic loci associated with CKD, yet much of the genetic basis remains unexplained. Part of the reason is that most GWASs have only assessed kidney function via single biomarkers such as estimated glomerular filtration rate (eGFR). This study employs a novel multi-phenotype approach, combinatorial Principal Component Analysis (cPCA), to better understand the genetic architecture of CKD. Utilizing a discovery cohort of white British individuals from the UK Biobank (n=337,112), we analyzed 21 CKD-related phenotypes using cPCA to generate over 2 million composite phenotypes (CPs). More than 46,000 CPs demonstrated superior performance in classifying clinical CKD compared to any single biomarker, and those CPs were most frequently comprised of eGFR, cystatin C, HbA1c, microalbuminuria, albumin, and LDL. GWASs of the top 1,000 CPs revealed seven novel genetic loci, withCST3andSH2B3successfully replicated in an independent Irish cohort (n=11,106). Notably, the index SNP of theSH2B3gene, which encodes a regulator in immune responses and cytokine signaling, is a loss-of-function variant with a combined beta of −0.046 and a p-value of 3.1E-56. These results highlight the effectiveness of a multi-phenotype approach in GWASs and implicate a novel functional variant in SH2B3 in CKD phenotypes.TRANSLATIONAL STATEMENTThe application of combinatorial Principal Component Analysis (cPCA) in our study has identifiedSH2B3as a novel genetic locus associated with chronic kidney disease (CKD). This discovery advances our understanding of CKD’s genetic architecture beyond single biomarker analyses, potentially leading to more precise diagnostic tools and personalized treatment strategies. Future research should focus on validating these findings in diverse populations and integrating cPCA-derived biomarkers into clinical practice to enhance CKD prediction and management, ultimately improving patient outcomes.

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Section: Introductionmentioning

confidence: 99%

A multi-phenotype approach implicatesSH2B3in the genetics of chronic kidney disease

Tran,

Sutherland,

Mallett

et al. 2024

Preprint

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“…Kidney dysfunctions can be observed with increased levels serum levels of cystatin C, creatinine or urea. The best marker studied till date for CKD is GFR which is measured using exogenous markers or estimated (eGFR) depending on the concentrations of endogenous filtration markers of serum creatinine and cystatin C [6,7]. For the longer survival of the individual diagnosed with ESRD requires dialysis or a kidney transplant to maintain the survival of the patient [8].…”

Section: Introductionmentioning

confidence: 99%

“…With the increase in the percentage of the disease numerous GWAS (Genome Wide Association Studies) have been conducted and many variants are identified in the last decade for CKD [7,[9][10][11][12]. This has also leaded to increase in testing out the different models of PRS (Polygenic Risk Score) for kidney risks in individual and in population cohort [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Polygenic Risk Score Comparative Analyses Reveals Risk Disparity of Genetic Predisposition to Chronic Kidney Disease- A Multi Ancestry Approach

Sharma¹,

Sharma²,

Gupta³

et al. 2022

Preprint

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Polygenic Risk Score (PRS) models are used extensively to find the population/individual risk towards disease. These predictive scores are of great help as risk scores if predicted earlier the life of individual can be saved from the chronic/ complex diseases. In this empirical assessments study, the polygenic risk score was calculated in three different ancestries (SAS, EAS and African Americans) based on more than three hundred markers. The risk score we observed indicated that average population risk scores are varied but on cumulating the ancestries the average risk score increased ~1.3 times than individual population average risk. The parameter which varies greatly while calculating the PRS is the ancestry; it should be prerequisite that individuals of same ancestry should be taken as a one population groups while calculating the scores.

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Monogenic and polygenic concepts in chronic kidney disease (CKD)

Jefferis,

Hudson,

Lacaze

et al. 2023

J Nephrol

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Kidney function is strongly influenced by genetic factors with both monogenic and polygenic factors contributing to kidney function. Monogenic disorders with primarily autosomal dominant inheritance patterns account for 10% of adult and 50% of paediatric kidney diseases. However, kidney function is also a complex trait with polygenic architecture, where genetic factors interact with environment and lifestyle factors. Family studies suggest that kidney function has significant heritability at 35–69%, capturing complexities of the genome with shared environmental factors. Genome-wide association studies estimate the single nucleotide polymorphism-based heritability of kidney function between 7.1 and 20.3%. These heritability estimates, measuring the extent to which genetic variation contributes to CKD risk, indicate a strong genetic contribution. Polygenic Risk Scores have recently been developed for chronic kidney disease and kidney function, and validated in large populations. Polygenic Risk Scores show correlation with kidney function but lack the specificity to predict individual-level changes in kidney function. Certain kidney diseases, such as membranous nephropathy and IgA nephropathy that have significant genetic components, may benefit most from polygenic risk scores for improved risk stratification. Genetic studies of kidney function also provide a potential avenue for the development of more targeted therapies and interventions. Understanding the development and validation of genomic scores is required to guide their implementation and identify the most appropriate potential implications in clinical practice. In this review, we provide an overview of the heritability of kidney function traits in population studies, explore both monogenic and polygenic concepts in kidney disease, with a focus on recently developed polygenic risk scores in kidney function and chronic kidney disease, and review specific diseases which are most amenable to incorporation of genomic scores. Graphical abstract

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

Cited by 3 publications

References 45 publications

A multi-phenotype approach implicatesSH2B3in the genetics of chronic kidney disease

A multi-phenotype approach implicatesSH2B3in the genetics of chronic kidney disease

Polygenic Risk Score Comparative Analyses Reveals Risk Disparity of Genetic Predisposition to Chronic Kidney Disease- A Multi Ancestry Approach

Monogenic and polygenic concepts in chronic kidney disease (CKD)

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