Li Man, Li Yong, Weeks Olivia, Mijatovic Vladan, Teumer Alexander, Huffman Jennifer E, Tromp Gerard, Fuchsberger Christian, Gorski Mathias, Lyytikäinen Leo-Pekka, Nutile Teresa, Sedaghat Sanaz, Sorice Rossella, Tin Adrienne, Yang Qiong, Ahluwalia Tarunveer S, Arking Dan E, Bihlmeyer Nathan A, Böger Carsten A, Carroll Robert J, Chasman Daniel I, Cornelis Marilyn C, Dehghan Abbas, Faul Jessica D, Feitosa Mary F, Gambaro Giovanni, Gasparini Paolo, Giulianini Franco, Heid Iris, Huang Jinyan, Imboden Medea, Jackson Anne U, Jeff Janina, Jhun Min A, Katz Ronit, Kifley Annette, Kilpeläinen Tuomas O, Kumar Ashish, Laakso Markku, Li-Gao Ruifang, Lohman Kurt, Lu Yingchang, Mägi Reedik, Malerba Giovanni, Mihailov Evelin, Mohlke Karen L, Mook-Kanamori Dennis O, Robino Antonietta, Ruderfer Douglas, Salvi Erika, Schick Ursula M, Schulz Christina-Alexandra, Smith Albert V, Smith Jennifer A, Traglia Michela, Yerges-Armstrong Laura M, Zhao Wei, Goodarzi Mark O, Kraja Aldi T, Liu Chunyu, Wessel Jennifer, Boerwinkle Eric, Borecki Ingrid B, Bork-Jensen Jette, Bottinger Erwin P, Braga Daniele, Brandslund Ivan, Brody Jennifer A, Campbell Archie, Carey David J, Christensen Cramer, Coresh Josef, Crook Errol, Curhan Gary C, Cusi Daniele, de Boer Ian H, de Vries Aiko P J, Denny Joshua C, Devuyst Olivier, Dreisbach Albert W, Endlich Karlhans, Esko Tõnu, Franco Oscar H, Fulop Tibor, Gerhard Glenn S, Glümer Charlotte, Gottesman Omri, Grarup Niels, Gudnason Vilmundur, Hansen Torben, Harris Tamara B, Hayward Caroline, Hocking Lynne, Hofman Albert, Hu Frank B, Husemoen Lise Lotte N, Jackson Rebecca D, Jørgensen Torben, Jørgensen Marit E, Kähönen Mika, Kardia Sharon L R, König Wolfgang, Kooperberg Charles, Kriebel Jennifer, Launer Lenore J, Lauritzen Torsten, Lehtimäki Terho, Levy Daniel, Linksted Pamela, Linneberg Allan, Liu Yongmei, Loos Ruth J F, Lupo Antonio, Meisinger Christine, Melander Olle, Metspalu Andres, Mitchell Paul, Nauck Matthias, Nürnberg Peter, Orho-Melander Marju, Parsa Afshin, Pedersen Oluf, Peters Annette, Peters Ulrike, Polasek Ozren, Porteous David, Probst-Hensch Nicole M, Psaty Bruce M, Qi Lu, Raitakari Olli T, Reiner Alex P, Rettig Rainer, Ridker Paul M, Rivadeneira Fernando, Rossouw Jacques E, Schmidt Frank, Siscovick David, Soranzo Nicole, Strauch Konstantin, Toniolo Daniela, Turner Stephen T, Uitterlinden André G, Ulivi Sheila, Velayutham Dinesh, Völker Uwe, Völzke Henry, Waldenberger Melanie, Wang Jie Jin, Weir David R, Witte Daniel, Kuivaniemi Helena, Fox Caroline S, Franceschini Nora, Goessling Wolfram, Köttgen Anna, Chu Audrey Y
Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland.
Division of Nephrology and Department of Human Genetics, University of Utah, Salt Lake City, Utah.
J Am Soc Nephrol. 2017 Mar;28(3):981-994. doi: 10.1681/ASN.2016020131. Epub 2016 Dec 5.
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 (: 111,666; : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (, , and ; <3.7×10), 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, (=5.4×10 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 and -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.
全基因组关联研究已经确定了50多个与肾功能相关的常见变异，但这些变异并不能完全解释估算肾小球滤过率（eGFR）的变化。我们基于慢性肾脏病基因组（CKDGen）联盟中欧洲血统参与者的血清肌酐水平（eGFRcrea），对Illumina外显子阵列的基因型与eGFR之间的关联进行了两阶段荟萃分析（发现队列：111,666人；验证队列：48,343人）。在单变异分析中，我们在7个与eGFRcrea相关的新位点鉴定出单核苷酸多态性（P<3.7×10⁻⁸），其中大多数是常见的且被注释为非同义变异。基于基因的分析确定了3个基因中的功能性罕见变异与eGFRcrea相关，包括与SOS Ras/Rho鸟嘌呤核苷酸交换因子2基因的新关联（通过序列核关联检验P=5.4×10⁻⁶）。在斑马鱼胚胎中的实验后续研究揭示了SOS2和SOS3基因敲低的胚胎肾脏中肾小球基因表达和肾小管形态的变化。这些发育异常与血液清除率改变和水肿患病率升高有关。本研究扩展了与肾功能相关的位点数量，并鉴定出在肾脏形成中具有潜在作用的新基因。
