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Genome-wide association and functional follow-up reveals new loci for kidney function.

ABSTRACT: Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

SUBMITTER: Pattaro C

PROVIDER: S-EPMC3315455 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Genome-wide association and functional follow-up reveals new loci for kidney function.

Pattaro Cristian C Köttgen Anna A Teumer Alexander A Garnaas Maija M Böger Carsten A CA Fuchsberger Christian C Olden Matthias M Chen Ming-Huei MH Tin Adrienne A Taliun Daniel D Li Man M Gao Xiaoyi X Gorski Mathias M Yang Qiong Q Hundertmark Claudia C Foster Meredith C MC O'Seaghdha Conall M CM Glazer Nicole N Isaacs Aaron A Liu Ching-Ti CT Smith Albert V AV O'Connell Jeffrey R JR Struchalin Maksim M Tanaka Toshiko T Li Guo G Johnson Andrew D AD Gierman Hinco J HJ Feitosa Mary M Hwang Shih-Jen SJ Atkinson Elizabeth J EJ Lohman Kurt K Cornelis Marilyn C MC Johansson Åsa Å Tönjes Anke A Dehghan Abbas A Chouraki Vincent V Holliday Elizabeth G EG Sorice Rossella R Kutalik Zoltan Z Lehtimäki Terho T Esko Tõnu T Deshmukh Harshal H Ulivi Sheila S Chu Audrey Y AY Murgia Federico F Trompet Stella S Imboden Medea M Kollerits Barbara B Pistis Giorgio G Harris Tamara B TB Launer Lenore J LJ Aspelund Thor T Eiriksdottir Gudny G Mitchell Braxton D BD Boerwinkle Eric E Schmidt Helena H Cavalieri Margherita M Rao Madhumathi M Hu Frank B FB Demirkan Ayse A Oostra Ben A BA de Andrade Mariza M Turner Stephen T ST Ding Jingzhong J Andrews Jeanette S JS Freedman Barry I BI Koenig Wolfgang W Illig Thomas T Döring Angela A Wichmann H-Erich HE Kolcic Ivana I Zemunik Tatijana T Boban Mladen M Minelli Cosetta C Wheeler Heather E HE Igl Wilmar W Zaboli Ghazal G Wild Sarah H SH Wright Alan F AF Campbell Harry H Ellinghaus David D Nöthlings Ute U Jacobs Gunnar G Biffar Reiner R Endlich Karlhans K Ernst Florian F Homuth Georg G Kroemer Heyo K HK Nauck Matthias M Stracke Sylvia S Völker Uwe U Völzke Henry H Kovacs Peter P Stumvoll Michael M Mägi Reedik R Hofman Albert A Uitterlinden Andre G AG Rivadeneira Fernando F Aulchenko Yurii S YS Polasek Ozren O Hastie Nick N Vitart Veronique V Helmer Catherine C Wang Jie Jin JJ Ruggiero Daniela D Bergmann Sven S Kähönen Mika M Viikari Jorma J Nikopensius Tiit T Province Michael M Ketkar Shamika S Colhoun Helen H Doney Alex A Robino Antonietta A Giulianini Franco F Krämer Bernhard K BK Portas Laura L Ford Ian I Buckley Brendan M BM Adam Martin M Thun Gian-Andri GA Paulweber Bernhard B Haun Margot M Sala Cinzia C Metzger Marie M Mitchell Paul P Ciullo Marina M Kim Stuart K SK Vollenweider Peter P Raitakari Olli O Metspalu Andres A Palmer Colin C Gasparini Paolo P Pirastu Mario M Jukema J Wouter JW Probst-Hensch Nicole M NM Kronenberg Florian F Toniolo Daniela D Gudnason Vilmundur V Shuldiner Alan R AR Coresh Josef J Schmidt Reinhold R Ferrucci Luigi L Siscovick David S DS van Duijn Cornelia M CM Borecki Ingrid I Kardia Sharon L R SL Liu Yongmei Y Curhan Gary C GC Rudan Igor I Gyllensten Ulf U Wilson James F JF Franke Andre A Pramstaller Peter P PP Rettig Rainer R Prokopenko Inga I Witteman Jacqueline C M JC Hayward Caroline C Ridker Paul P Parsa Afshin A Bochud Murielle M Heid Iris M IM Goessling Wolfram W Chasman Daniel I DI Kao W H Linda WH Fox Caroline S CS

PLoS genetics 20120329 3

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte ...[more]

PMID: 22479191

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Project description:Genome-wide association studies (GWAS) of kidney function have uncovered hundreds of loci, primarily in populations of European ancestry. We have undertaken the first continental African GWAS of estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We conducted GWAS of eGFR in 3288 East Africans from the Uganda General Population Cohort (GPC) and replicated in 8224 African Americans from the Women's Health Initiative. Loci attaining genome-wide significant evidence for association (P < 5 × 10-8) were followed up with Bayesian fine-mapping to localize potential causal variants. The predictive power of a genetic risk score (GRS) constructed from previously reported trans-ancestry eGFR lead single nucleotide polymorphism (SNPs) was evaluated in the Uganda GPC. We identified and validated two eGFR loci. At the glycine amidinotransferase (GATM) locus, the association signal (lead SNP rs2433603, P = 1.0 × 10-8) in the Uganda GPC GWAS was distinct from previously reported signals at this locus. At the haemoglobin beta (HBB) locus, the association signal (lead SNP rs141845179, P = 3.0 × 10-8) has been previously reported. The lead SNP at the HBB locus accounted for 88% of the posterior probability of causality after fine-mapping, but did not colocalise with kidney expression quantitative trait loci. The trans-ancestry GRS of eGFR was not significantly predictive into the Ugandan population. In the first GWAS of eGFR in continental Africa, we validated two previously reported loci at GATM and HBB. At the GATM locus, the association signal was distinct from that previously reported. These results demonstrate the value of performing GWAS in continental Africans, providing a rich genomic resource to larger consortia for further discovery and fine-mapping. The study emphasizes that additional large-scale efforts in Africa are warranted to gain further insight into the genetic architecture of CKD.

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Genome-wide association and functional follow-up reveals new loci for kidney function.

Publications

Genome-wide association and functional follow-up reveals new loci for kidney function.

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