PUBLICATION

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, J.E., Tromp, G., Fuchsberger, C., Gorski, M., Lyytikäinen, L.P., Nutile, T., Sedaghat, S., Sorice, R., Tin, A., Yang, Q., Ahluwalia, T.S., Arking, D.E., Bihlmeyer, N.A., Böger, C.A., Carroll, R.J., Chasman, D.I., Cornelis, M.C., Dehghan, A., Faul, J.D., Feitosa, M.F., Gambaro, G., Gasparini, P., Giulianini, F., Heid, I., Huang, J., Imboden, M., Jackson, A.U., Jeff, J., Jhun, M.A., Katz, R., Kifley, A., Kilpeläinen, T.O., Kumar, A., Laakso, M., Li-Gao, R., Lohman, K., Lu, Y., Mägi, R., Malerba, G., Mihailov, E., Mohlke, K.L., Mook-Kanamori, D.O., Robino, A., Ruderfer, D., Salvi, E., Schick, U.M., Schulz, C.A., Smith, A.V., Smith, J.A., Traglia, M., Yerges-Armstrong, L.M., Zhao, W., Goodarzi, M.O., Kraja, A.T., Liu, C., Wessel, J., Boerwinkle, E., Borecki, I.B., Bork-Jensen, J., Bottinger, E.P., Braga, D., Brandslund, I., Brody, J.A., Campbell, A., Carey, D.J., Christensen, C., Coresh, J., Crook, E., Curhan, G.C., Cusi, D., de Boer, I.H., de Vries, A.P., Denny, J.C., Devuyst, O., Dreisbach, A.W., Endlich, K., Esko, T., Franco, O.H., Fulop, T., Gerhard, G.S., Glümer, C., Gottesman, O., Grarup, N., Gudnason, V., Harris, T.B., Hayward, C., Hocking, L., Hofman, A., Hu, F.B., Husemoen, L.L., Jackson, R.D., Jørgensen, T., Jørgensen, M.E., Kähönen, M., Kardia, S.L., König, W., Kooperberg, C., Kriebel, J., Launer, L.J., Lauritzen, T., Lehtimäki, T., Levy, D., Linksted, P., Linneberg, A., Liu, Y., Loos, R.J., Lupo, A., Meisinger, C., Melander, O., Metspalu, A., Mitchell, P., Nauck, M., Nürnberg, P., Orho-Melander, M., Parsa, A., Pedersen, O., Peters, A., Peters, U., Polasek, O., Porteous, D., Probst-Hensch, N.M., Psaty, B.M., Qi, L., Raitakari, O.T., Reiner, A.P., Rettig, R., Ridker, P.M., Rivadeneira, F., Rossouw, J.E., Schmidt, F., Siscovick, D., Soranzo, N., Strauch, K., Toniolo, D., Turner, S.T., Uitterlinden, A.G., Ulivi, S., Velayutham, D., Völker, U., Völzke, H., Waldenberger, M., Wang, J.J., Weir, D.R., Witte, D., Kuivaniemi, H., Fox, C.S., Franceschini, N., Goessling, W., Köttgen, A., Chu, A.Y.
ID
ZDB-PUB-161207-4
Date
2017
Source
Journal of the American Society of Nephrology : JASN   28(3): 981-994 (Journal)
Registered Authors
Goessling, Wolfram, Imboden, Medea
Keywords
human genetics, kidney development, renal function
MeSH Terms
  • Animals
  • Exome/genetics*
  • Genetic Loci
  • Genome-Wide Association Study
  • Glomerular Filtration Rate/genetics*
  • Humans
  • Kidney/embryology*
  • Protein Tyrosine Phosphatases/genetics*
  • Proto-Oncogene Proteins/genetics*
  • Son of Sevenless Proteins/genetics*
  • Zebrafish
PubMed
27920155 Full text @ J. Am. Soc. Nephrol.
Citation
Li, M., Li, Y., Weeks, O., Mijatovic, V., Teumer, A., Huffman, J.E., Tromp, G., Fuchsberger, C., Gorski, M., Lyytikäinen, L.P., Nutile, T., Sedaghat, S., Sorice, R., Tin, A., Yang, Q., Ahluwalia, T.S., Arking, D.E., Bihlmeyer, N.A., Böger, C.A., Carroll, R.J., Chasman, D.I., Cornelis, M.C., Dehghan, A., Faul, J.D., Feitosa, M.F., Gambaro, G., Gasparini, P., Giulianini, F., Heid, I., Huang, J., Imboden, M., Jackson, A.U., Jeff, J., Jhun, M.A., Katz, R., Kifley, A., Kilpeläinen, T.O., Kumar, A., Laakso, M., Li-Gao, R., Lohman, K., Lu, Y., Mägi, R., Malerba, G., Mihailov, E., Mohlke, K.L., Mook-Kanamori, D.O., Robino, A., Ruderfer, D., Salvi, E., Schick, U.M., Schulz, C.A., Smith, A.V., Smith, J.A., Traglia, M., Yerges-Armstrong, L.M., Zhao, W., Goodarzi, M.O., Kraja, A.T., Liu, C., Wessel, J., Boerwinkle, E., Borecki, I.B., Bork-Jensen, J., Bottinger, E.P., Braga, D., Brandslund, I., Brody, J.A., Campbell, A., Carey, D.J., Christensen, C., Coresh, J., Crook, E., Curhan, G.C., Cusi, D., de Boer, I.H., de Vries, A.P., Denny, J.C., Devuyst, O., Dreisbach, A.W., Endlich, K., Esko, T., Franco, O.H., Fulop, T., Gerhard, G.S., Glümer, C., Gottesman, O., Grarup, N., Gudnason, V., Harris, T.B., Hayward, C., Hocking, L., Hofman, A., Hu, F.B., Husemoen, L.L., Jackson, R.D., Jørgensen, T., Jørgensen, M.E., Kähönen, M., Kardia, S.L., König, W., Kooperberg, C., Kriebel, J., Launer, L.J., Lauritzen, T., Lehtimäki, T., Levy, D., Linksted, P., Linneberg, A., Liu, Y., Loos, R.J., Lupo, A., Meisinger, C., Melander, O., Metspalu, A., Mitchell, P., Nauck, M., Nürnberg, P., Orho-Melander, M., Parsa, A., Pedersen, O., Peters, A., Peters, U., Polasek, O., Porteous, D., Probst-Hensch, N.M., Psaty, B.M., Qi, L., Raitakari, O.T., Reiner, A.P., Rettig, R., Ridker, P.M., Rivadeneira, F., Rossouw, J.E., Schmidt, F., Siscovick, D., Soranzo, N., Strauch, K., Toniolo, D., Turner, S.T., Uitterlinden, A.G., Ulivi, S., Velayutham, D., Völker, U., Völzke, H., Waldenberger, M., Wang, J.J., Weir, D.R., Witte, D., Kuivaniemi, H., Fox, C.S., Franceschini, N., Goessling, W., Köttgen, A., Chu, A.Y. (2017) SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.. Journal of the American Society of Nephrology : JASN. 28(3):981-994.
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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