A1 Refereed original research article in a scientific journal
SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function
Authors: Li M, Li Y, Weeks O, Mijatovic V, Teumer A, Huffman JE, Tromp G, Fuchsberger C, Gorski M, Lyytikainen LP, Nutile T, Sedaghat S, Sorice R, Tin A, Yang Q, Ahluwalia TS, Arking DE, Bihlmeyer NA, Boger CA, Carroll RJ, Chasman DI, Comelis MC, Dehghan A, Faul JD, Feitosa MF, Gambaro G, Gasparini P, Giulianini F, Heid I, Huang JY, Imboden M, Jackson AU, Jeff J, Jhun MA, Katz R, Kifley A, Kilpelainen T, Kumar A, Laakso M, Li-Gao RF, Lohman K, Lu YC, Magi R, Malerba G, Mihailov E, Mohlke KL, Mook-Kanamori DO, Robino A, Ruderfer D, Salvi E, Schick UM, Schulz CA, Smith AV, Smith JA, Traglia M, Yerges-Armstrong LM, Zhao W, Goodarzi MO, Kraja AT, Liu CY, Wessel J, Boerwinkle E, Borecki IB, Bork-Jensen J, Bottinger EP, Braga D, Brandslund I, Brody JA, Campbell A, Carey DJ, Christensen C, Coresh J, Crook E, Curhan GC, Cusi D, de Boer IH, de Vries APJ, Denny JC, Devuyst O, Dreisbach AW, Endlich K, Esko T, Franco OH, Fulop T, Gerhard GS, Glumer C, Gottesman O, Grarup N, Gudnason V, Hansen T, Harris TB, Hayward C, Hocking L, Hofman A, Hu FB, Husemoen LLN, Jackson RD, Jorgensen T, Jorgensen ME, Kahonen M, Kardia SLR, Konig W, Kooperberg C, Kriebel J, Launer LJ, Lauritzen T, Lehtimaki T, Levy D, Linksted P, Linneberg A, Liu YM, Loos RJF, Lupo A, Meisinger C, Melander O, Metspalu A, Mitchell P, Nauck M, Nurnberg P, Orho-Melander M, Parsa A, Pedersen O, Peters A, Peters U, Polasek O, Porteous D, Probst-Hensch NM, Psaty BM, Qi L, Raitakari OT, Reiner AP, Rettig R, Ridker PM, Rivadeneira F, Rossouw JE, Schmidt F, Siscovick D, Soranzo N, Strauch K, Toniolo D, Turner ST, Uitterlinden AG, Ulivi S, Velayutham D, Volker U, Volzke H, Waldenberger M, Wang JJ, Weir DR, Witte D, Kuivaniemi H, Fox CS, Franceschini N, Goessling W, Kottgen A, Chu AY, Fox CS, Franceschini N, Goessling W, Kottgen A, Chu AY
Publisher: AMER SOC NEPHROLOGY
Publication year: 2017
Journal: Journal of the American Society of Nephrology
Journal name in source: JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Journal acronym: J AM SOC NEPHROL
Volume: 28
Issue: 3
First page : 981
Last page: 994
Number of pages: 14
ISSN: 1046-6673
eISSN: 1533-3450
DOI: https://doi.org/10.1681/ASN.2016020131
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 (n(stage1);111,666;n(stage2): 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; P-stage1<3.7 x10(-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=5.4x 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.
