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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    ABSTRACT: Advances in genomics and next-generation sequencing have provided clinical researchers with unprecedented opportunities to understand the molecular basis of human genetic disorders. This abundance of information places new requirements on traditional disease models, which have the potential to be used to confirm newly identified pathogenic mutations and test the efficacy of emerging therapies. The unique attributes of zebrafish are being increasingly leveraged to create functional disease models, facilitate drug discovery, and provide critical scientific bases for the development of new clinical tools for the diagnosis and treatment of human disease. In this short review and the accompanying poster, we highlight a few illustrative examples of the applications of the zebrafish model to the study of human health and disease.
    No preview · Article · Jul 2014 · Disease Models and Mechanisms
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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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    ABSTRACT: Regenerative medicine has the promise to alleviate morbidity and mortality caused by organ dysfunction, longstanding injury and trauma. Although regenerative approaches for a few diseases have been highly successful, some organs either do not regenerate well or have no current treatment approach to harness their intrinsic regenerative potential. In this Review, we describe the modeling of human disease and tissue repair in zebrafish, through the discovery of disease-causing genes using classical forward-genetic screens and by modulating clinically relevant phenotypes through chemical genetic screening approaches. Furthermore, we present an overview of those organ systems that regenerate well in zebrafish in contrast to mammalian tissue, as well as those organs in which the regenerative potential is conserved from fish to mammals, enabling drug discovery in preclinical disease-relevant models. We provide two examples from our own work in which the clinical translation of zebrafish findings is either imminent or has already proven successful. The promising results in multiple organs suggest that further insight into regenerative mechanisms and novel clinically relevant therapeutic approaches will emerge from zebrafish research in the future.
    Full-text · Article · Jul 2014 · Disease Models and Mechanisms
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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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    ABSTRACT: Genome-Wide Association Studies are widely used to correlate phenotypic traits with genetic variants. These studies usually compare the genetic variation between two groups to single out certain Single Nucleotide Polymorphisms (SNPs) that are linked to a phenotypic variation in one of the groups. However, it is necessary to have a large enough sample size to find statistically significant correlations. Direct-To-Consumer (DTC) genetic testing can supply additional data: DTC-companies offer the analysis of a large amount of SNPs for an individual at low cost without the need to consult a physician or geneticist. Over 100,000 people have already been genotyped through Direct-To-Consumer genetic testing companies. However, this data is not public for a variety of reasons and thus cannot be used in research. It seems reasonable to create a central open data repository for such data. Here we present the web platform openSNP, an open database which allows participants of Direct-To-Consumer genetic testing to publish their genetic data at no cost along with phenotypic information. Through this crowdsourced effort of collecting genetic and phenotypic information, openSNP has become a resource for a wide area of studies, including Genome-Wide Association Studies. openSNP is hosted at, and the code is released under MIT-license at
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