Genome-wide polygenic risk predictors for kidney disease

Liu, Lili; Kiryluk, Krzysztof

doi:10.1038/s41581-018-0067-6

Cited by 37 publications

(19 citation statements)

References 10 publications

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“…These observations have important implications for the implementation of kidney precision medicine. For example, the approaches that combine diagnostic sequencing with polygenic risk scores for specific subtypes of kidney diseases may be better suited for clinical risk stratification compared to polygenic risk scores based on GWAS for eGFR alone 63 . Future improvements of ephenotyping for CKD are likely to involve automated CKD subtype determination, and more accurate methods for estimation of GFR in adult and pediatric patients of diverse ancestral backgrounds.…”

Section: Discussionmentioning

confidence: 99%

Medical records-based chronic kidney disease phenotype for clinical care and “big data” observational and genetic studies

et al. 2021

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Chronic Kidney Disease (CKD) represents a slowly progressive disorder that is typically silent until late stages, but early intervention can significantly delay its progression. We designed a portable and scalable electronic CKD phenotype to facilitate early disease recognition and empower large-scale observational and genetic studies of kidney traits. The algorithm uses a combination of rule-based and machine-learning methods to automatically place patients on the staging grid of albuminuria by glomerular filtration rate (“A-by-G” grid). We manually validated the algorithm by 451 chart reviews across three medical systems, demonstrating overall positive predictive value of 95% for CKD cases and 97% for healthy controls. Independent case-control validation using 2350 patient records demonstrated diagnostic specificity of 97% and sensitivity of 87%. Application of the phenotype to 1.3 million patients demonstrated that over 80% of CKD cases are undetected using ICD codes alone. We also demonstrated several large-scale applications of the phenotype, including identifying stage-specific kidney disease comorbidities, in silico estimation of kidney trait heritability in thousands of pedigrees reconstructed from medical records, and biobank-based multicenter genome-wide and phenome-wide association studies.

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Section: Discussionmentioning

confidence: 99%

Medical records-based chronic kidney disease phenotype for clinical care and “big data” observational and genetic studies

et al. 2021

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“…In this study, generation and validation of genome-wide risk scores for the aforementioned traits identified a relative risk for disease development comparable to monogenic causes (59). Nevertheless, large-scale investigations including GWAS are needed before polygenic risk scores can be implemented in clinical medicine (58), and for CAKUT in particular.…”

Section: Common Variants In Congenital Anomalies Of the Kidney And Urmentioning

confidence: 89%

“…However, with the improvement of genetic methods, bioinformatic tools, and statistical genetic analyses, the next step is to generate oligo-or polygenic risk scores from GWAS data. Polygenic risk scores combine the sum of all known variants to calculate an overall risk of developing a particular disease (58). Recently, this approach was used for coronary artery disease, inflammatory bowel disease, and diabetes mellitus (59).…”

Section: Common Variants In Congenital Anomalies Of the Kidney And Urmentioning

confidence: 99%

Clinical Integration of Genome Diagnostics for Congenital Anomalies of the Kidney and Urinary Tract

Westland

Renkema

Knoers

2020

CJASN

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Revolutions in genetics, epigenetics, and bioinformatics are currently changing the outline of diagnostics and clinical medicine. From a nephrologist's perspective, individuals with congenital anomalies of the kidney and urinary tract (CAKUT) are an important patient category: not only is CAKUT the predominant cause of kidney failure in children and young adults, but the strong phenotypic and genotypic heterogeneity of kidney and urinary tract malformations has hampered standardization of clinical decision making until now. However, patients with CAKUT may benefit from precision medicine, including an integrated diagnostics trajectory, genetic counseling, and personalized management to improve clinical outcomes of developmental kidney and urinary tract defects. In this review, we discuss the present understanding of the molecular etiology of CAKUT and the currently available genome diagnostic modalities in the clinical care of patients with CAKUT. Finally, we discuss how clinical integration of findings from large-scale genetic, epigenetic, and gene-environment interaction studies may improve the prognosis of all individuals with CAKUT.

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“…The clinical utility of genetic scores for complex traits is an active area of research, both in terms of identifying individuals with a high genetic predisposition for a disease and, in combination with clinical measures, to optimize prevention and treatments (52). Novel methods for computing genetic scores using a large number of variants across the genome beyond the index variants from GWAS, termed genome-wide polygenic scores, may increase prediction accuracy (33,(53)(54)(55). The challenges discussed above also influence the potential clinical utility of genetic scores of kidney function-related traits.…”

Section: Making Genetic Scores Of Kidney Function-related Traits Clinmentioning

confidence: 99%

“…Other challenges to eventually making kidney functionrelated genetic score clinically useful are similar to those for other complex traits, including the need for absolute risk prediction for a given time frame, which is more relevant for clinical decision and requires the integration of prospective disease outcome with other patient characteristics (54). In addition, the availability of large datasets from non-European ancestry populations for the assessment of prediction accuracy has been limited (52).…”

Section: Making Genetic Scores Of Kidney Function-related Traits Clinmentioning

confidence: 99%

Genome-Wide Association Studies of CKD and Related Traits

Tin

Köttgen

2020

CJASN

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The past few years have seen major advances in genome-wide association studies (GWAS) of CKD and kidney function–related traits in several areas: increases in sample size from >100,000 to >1 million, enabling the discovery of >250 associated genetic loci that are highly reproducible; the inclusion of participants not only of European but also of non-European ancestries; and the use of advanced computational methods to integrate additional genomic and other unbiased, high-dimensional data to characterize the underlying genetic architecture and prioritize potentially causal genes and variants. Together with other large-scale biobank and genetic association studies of complex traits, these GWAS of kidney function–related traits have also provided novel insight into the relationship of kidney function to other diseases with respect to their genetic associations, genetic correlation, and directional relationships. A number of studies also included functional experiments using model organisms or cell lines to validate prioritized potentially causal genes and/or variants. In this review article, we will summarize these recent GWAS of CKD and kidney function–related traits, explain approaches for downstream characterization of associated genetic loci and the value of such computational follow-up analyses, and discuss related challenges along with potential solutions to ultimately enable improved treatment and prevention of kidney diseases through genetics.

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Genome-wide polygenic risk predictors for kidney disease

Cited by 37 publications

References 10 publications

Medical records-based chronic kidney disease phenotype for clinical care and “big data” observational and genetic studies

Medical records-based chronic kidney disease phenotype for clinical care and “big data” observational and genetic studies

Clinical Integration of Genome Diagnostics for Congenital Anomalies of the Kidney and Urinary Tract

Genome-Wide Association Studies of CKD and Related Traits

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