Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function

Institute of Genetic Medicine, European Academy of Bozen/Bolzano (EURAC) and Affiliated Institute of the University of Lübeck, Bolzano, Italy.
PLoS Genetics (Impact Factor: 7.53). 03/2012; 8(3):e1002584. DOI: 10.1371/journal.pgen.1002584
Source: PubMed


Author Summary
Chronic kidney disease (CKD) is an important public health problem with a hereditary component. We performed a new genome-wide association study in up to 130,600 European ancestry individuals to identify genes that may influence kidney function, specifically genes that may influence kidney function differently depending on sex, age, hypertension, and diabetes status of individuals. We uncovered 6 new loci associated with estimated glomerular filtration rate (eGFR), the primary measure of renal function, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. CDK12 effect was stronger in younger and absent in older individuals. MPPED2, DDX1, SLC47A1, and CDK12 loci were associated with eGFR in African ancestry samples as well, highlighting the cross-ethnicity validity of our findings. Using the zebrafish model, we performed morpholino knockdown of mpped2 and casp9 in zebrafish embryos and revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. These results further our understanding of the pathogenesis of CKD and provide insights into potential novel mechanisms of disease.

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Available from: Andre Franke, Mar 05, 2014
    • "In addition to the exploration of genes that are known to impact human health, the powerful zebrafish model also contributes to the discovery of previously unidentified disease genes. For example, candidate genes obtained from large genome-wide association studies of kidney and platelet dysfunction have been screened in zebrafish to establish specific phenotypic connections to these genetic risk profiles (Pattaro et al., 2012; Gieger et al., 2011). Reverse genetics screens (Ryan et al., 2013; Huang et al., 2013; Kettleborough et al., 2013) have also shed light on new molecular partners of known disease genes, not only providing researchers with a greater understanding of the pathways involved in human disorders, but also providing new genetic targets for human geneticists to explore in patients with clinical diagnoses in the absence of a known pathogenic mutation. "
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    • "Transient knockdown can be combined with ENU or TILLING mutations to eliminate functional redundancy or perform epistasis experiments. More recently, a series of studies have taken advantage of the speed of transient knockdown to assess the functional relevancy of candidate disease genes identified through patient genome-wide association studies on a variety of clinical phenotypes, including platelet production (Gieger et al., 2011), chronic kidney disease (Liu et al., 2011; Pattaro et al., 2012) and liver function (Liu et al., 2013). All these investigations revealed several genes that affect organ development, function and/or susceptibility to disease; this information can be used to conduct further chemical and/or genetic interaction or suppressor screens in zebrafish or to guide follow-up studies in mammalian models. "
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    • "This enables GWAS to find SNPs which are significantly overrepresented in patients and associates those SNPs with a trait or illness. While the method does not allow inference of causal differences but merely identifies correlations, it can serve as a valuable tool for the unbiased discovery of candidate loci, which then can be checked up in functional follow-up studies [6], leading to a deeper understanding of diseases and thus potentially to new drug targets. The first GWAS was published in 2005 and compared age-related macular degeneration in contrast to a healthy control group [7]. "
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