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.

SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function / M. Li, Y. Li, O. Weeks, V. Mijatovic, A. Teumer, J.E. Huffman, G. Tromp, C. Fuchsberger, M. Gorski, L.P. Lyytikainen, T. Nutile, S. Sedaghat, R. Sorice, A. Tin, Q. Yang, T.S. Ahluwalia, D.E. Arking, N.A. Bihlmeyer, C.A. Boger, R.J. Carroll, D.I. Chasman, M.C. Comelis, A. Dehghan, J.D. Faul, M.F. Feitosa, G. Gambaro, P. Gasparini, F. Giulianini, I. Heid, J.Y. Huang, M. Imboden, A.U. Jackson, J. Jeff, M.A. Jhun, R. Katz, A. Kifley, T. Kilpelainen, A. Kumar, M. Laakso, R.F. Li Gao, K. Lohman, Y.C. Lu, R. Magi, G. Malerba, E. Mihailov, K.L. Mohlke, D.O. Mook Kanamori, A. Robino, D. Ruderfer, E. Salvi, U.M. Schick, C.A. Schulz, A.V. Smith, J.A. Smith, M. Traglia, L.M. Yerges Armstrong, W. Zhao, M.O. Goodarzi, A.T. Kraja, C.Y. Liu, J. Wessel, E. Boerwinkle, I.B. Borecki, J. Bork Jensen, E.P. Bottinger, D. Braga, I. Brandslund, J.A. Brody, A. Campbell, D.J. Carey, C. Christensen, J. Coresh, E. Crook, G.C. Curhan, D. Cusi, I.H. de Boer, A.P.J. de Vries, J.C. Denny, O. Devuyst, A.W. Dreisbach, K. Endlich, T. Esko, O.H. Franco, T. Fulop, G.S. Gerhard, C. Glumer, O. Gottesman, N. Grarup, V. Gudnason, T. Hansen, T.B. Harris, C. Hayward, L. Hocking, A. Hofman, F.B. Hu, L.L.N. Husemoen, R.D. Jackson, T. Jorgensen, M.E. Jorgensen, M. Kahonen, S.L.R. Kardia, W. Konig, C. Kooperberg, J. Kriebel, L.J. Launer, T. Lauritzen, T. Lehtimaki, D. Levy, P. Linksted, A. Linneberg, Y.M. Liu, R.J.F. Loos, A. Lupo, C. Meisinger, O. Melander, A. Metspalu, P. Mitchell, M. Nauck, P. Nurnberg, M. Orho Melander, A. Parsa, O. Pedersen, A. Peters, U. Peters, O. Polasek, D. Porteous, N.M. Probst Hensch, B.M. Psaty, L. Qi, O.T. Raitakari, A.P. Reiner, R. Rettig, P.M. Ridker, F. Rivadeneira, J.E. Rossouw, F. Schmidt, D. Siscovick, N. Soranzo, K. Strauch, D. Toniolo, S.T. Turner, A.G. Uitterlinden, S. Ulivi, D. Velayutham, U. Volker, H. Volzke, M. Waldenberger, J.J. Wang, D.R. Weir, D. Witte, H. Kuivaniemi, C.S. Fox, N. Franceschini, W. Goessling, A. Kottgen, A.Y. Chu. - In: JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY. - ISSN 1046-6673. - 28(2017 Jan), pp. 981-994. [10.1681/ASN.2016020131]

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

E. Salvi;D. Braga;D. Cusi;N. Soranzo;D. Velayutham;
2017-01

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.
human genetics; kidney development; renal function
Settore MED/03 - Genetica Medica
Settore MED/01 - Statistica Medica
Settore MED/14 - Nefrologia
5-dic-2016
Article (author)
File in questo prodotto:
File Dimensione Formato  
SOS2_ACP1_2016.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 1.29 MB
Formato Adobe PDF
1.29 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/462909
Citazioni
  • ???jsp.display-item.citation.pmc??? 21
  • Scopus 29
  • ???jsp.display-item.citation.isi??? 30
social impact