Journal
NATURE REVIEWS NEPHROLOGY
Volume 16, Issue 11, Pages 628-640Publisher
NATURE RESEARCH
DOI: 10.1038/s41581-020-0298-1
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Funding
- NIH National Institute of Diabetes and Digestive and Kidney Diseases [R01DK076077, R01 DK087635, DP3 DK108220]
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Sullivan and Susztak examine the process of translating data on genetic variants associated with common kidney diseases into information about the underlying disease mechanisms. The authors propose that identification of causal variants, genetic regulatory mechanisms, target-gene products and disease-associated phenotypes is crucial to this process. Genome-wide association studies (GWAS) have identified hundreds of loci associated with kidney-related traits such as glomerular filtration rate, albuminuria, hypertension, electrolyte and metabolite levels. However, these impressive, large-scale mapping approaches have not always translated into an improved understanding of disease or development of novel therapeutics. GWAS have several important limitations. Nearly all disease-associated risk loci are located in the non-coding region of the genome and therefore, their target genes, affected cell types and regulatory mechanisms remain unknown. Genome-scale approaches can be used to identify associations between DNA sequence variants and changes in gene expression (quantified through bulk and single-cell methods), gene regulation and other molecular quantitative trait studies, such as chromatin accessibility, DNA methylation, protein expression and metabolite levels. Data obtained through these approaches, used in combination with robust computational methods, can deliver robust mechanistic inferences for translational exploitation. Understanding the genetic basis of common kidney diseases means having a comprehensive picture of the genes that have a causal role in disease development and progression, of the cells, tissues and organs in which these genes act to affect the disease, of the cellular pathways and mechanisms that drive disease, and of potential targets for disease prevention, detection and therapy.
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