Dataset Information

SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.

ABSTRACT: Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10-7), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10-8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

SUBMITTER: Li M

PROVIDER: S-EPMC5328154 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.

Li Man M Li Yong Y Weeks Olivia O Mijatovic Vladan V Teumer Alexander A Huffman Jennifer E JE Tromp Gerard G Fuchsberger Christian C Gorski Mathias M Lyytikäinen Leo-Pekka LP Nutile Teresa T Sedaghat Sanaz S Sorice Rossella R Tin Adrienne A Yang Qiong Q Ahluwalia Tarunveer S TS Arking Dan E DE Bihlmeyer Nathan A NA Böger Carsten A CA Carroll Robert J RJ Chasman Daniel I DI Cornelis Marilyn C MC Dehghan Abbas A Faul Jessica D JD Feitosa Mary F MF Gambaro Giovanni G Gasparini Paolo P Giulianini Franco F Heid Iris I Huang Jinyan J Imboden Medea M Jackson Anne U AU Jeff Janina J Jhun Min A MA Katz Ronit R Kifley Annette A Kilpeläinen Tuomas O TO Kumar Ashish A Laakso Markku M Li-Gao Ruifang R Lohman Kurt K Lu Yingchang Y Mägi Reedik R Malerba Giovanni G Mihailov Evelin E Mohlke Karen L KL Mook-Kanamori Dennis O DO Robino Antonietta A Ruderfer Douglas D Salvi Erika E Schick Ursula M UM Schulz Christina-Alexandra CA Smith Albert V AV Smith Jennifer A JA Traglia Michela M Yerges-Armstrong Laura M LM Zhao Wei W Goodarzi Mark O MO Kraja Aldi T AT Liu Chunyu C Wessel Jennifer J Boerwinkle Eric E Borecki Ingrid B IB Bork-Jensen Jette J Bottinger Erwin P EP Braga Daniele D Brandslund Ivan I Brody Jennifer A JA Campbell Archie A Carey David J DJ Christensen Cramer C Coresh Josef J Crook Errol E Curhan Gary C GC Cusi Daniele D de Boer Ian H IH de Vries Aiko P J AP Denny Joshua C JC Devuyst Olivier O Dreisbach Albert W AW Endlich Karlhans K Esko Tõnu T Franco Oscar H OH Fulop Tibor T Gerhard Glenn S GS Glümer Charlotte C Gottesman Omri O Grarup Niels N Gudnason Vilmundur V Hansen Torben T Harris Tamara B TB Hayward Caroline C Hocking Lynne L Hofman Albert A Hu Frank B FB Husemoen Lise Lotte N LL Jackson Rebecca D RD Jørgensen Torben T Jørgensen Marit E ME Kähönen Mika M Kardia Sharon L R SL König Wolfgang W Kooperberg Charles C Kriebel Jennifer J Launer Lenore J LJ Lauritzen Torsten T Lehtimäki Terho T Levy Daniel D Linksted Pamela P Linneberg Allan A Liu Yongmei Y Loos Ruth J F RJ Lupo Antonio A Meisinger Christine C Melander Olle O Metspalu Andres A Mitchell Paul P Nauck Matthias M Nürnberg Peter P Orho-Melander Marju M Parsa Afshin A Pedersen Oluf O Peters Annette A Peters Ulrike U Polasek Ozren O Porteous David D Probst-Hensch Nicole M NM Psaty Bruce M BM Qi Lu L Raitakari Olli T OT Reiner Alex P AP Rettig Rainer R Ridker Paul M PM Rivadeneira Fernando F Rossouw Jacques E JE Schmidt Frank F Siscovick David D Soranzo Nicole N Strauch Konstantin K Toniolo Daniela D Turner Stephen T ST Uitterlinden André G AG Ulivi Sheila S Velayutham Dinesh D Völker Uwe U Völzke Henry H Waldenberger Melanie M Wang Jie Jin JJ Weir David R DR Witte Daniel D Kuivaniemi Helena H Fox Caroline S CS Franceschini Nora N Goessling Wolfram W Köttgen Anna A Chu Audrey Y AY

Journal of the American Society of Nephrology : JASN 20161205 3

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identifie ...[more]

PMID: 27920155

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Project description:ChIP-seq has become the primary method for identifying in vivo protein-DNA interactions on a genome-wide scale, with nearly 800 publications involving the technique appearing in PubMed as of December 2012. Individually and in aggregate, these data are an important and information-rich resource. However, uncertainties about data quality confound their use by the wider research community. Recently, the Encyclopedia of DNA Elements (ENCODE) project developed and applied metrics to objectively measure ChIP-seq data quality. The ENCODE quality analysis was useful for flagging datasets for closer inspection, eliminating or replacing poor data, and for driving changes in experimental pipelines. There had been no similarly systematic quality analysis of the large and disparate body of published ChIP-seq profiles. Here, we report a uniform analysis of vertebrate transcription factor ChIP-seq datasets in the Gene Expression Omnibus (GEO) repository as of April 1, 2012. The majority (55%) of datasets scored as being highly successful, but a substantial minority (20%) were of apparently poor quality, and another ?25% were of intermediate quality. We discuss how different uses of ChIP-seq data are affected by specific aspects of data quality, and we highlight exceptional instances for which the metric values should not be taken at face value. Unexpectedly, we discovered that a significant subset of control datasets (i.e., no immunoprecipitation and mock immunoprecipitation samples) display an enrichment structure similar to successful ChIP-seq data. This can, in turn, affect peak calling and data interpretation. Published datasets identified here as high-quality comprise a large group that users can draw on for large-scale integrated analysis. In the future, ChIP-seq quality assessment similar to that used here could guide experimentalists at early stages in a study, provide useful input in the publication process, and be used to stratify ChIP-seq data for different community-wide uses.

Dataset Information

SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.

Publications

<i>SOS2</i> and <i>ACP1</i> Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.

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