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
  • Glomerular Filtration Rate/genetics*
  • Genome-Wide Association Study
  • Animals
  • Son of Sevenless Proteins/genetics*
  • Zebrafish
  • Genetic Loci
  • Humans
  • Protein Tyrosine Phosphatases/genetics*
  • Exome/genetics*
  • Proto-Oncogene Proteins/genetics*
  • Kidney/embryology*
(all 11)
PubMed
27920155 Full text @ J. Am. Soc. Nephrol.
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
No images available
Show all Figures
Expression
Phenotype
Fish Conditions Stage Phenotype Figure
WT + MO1-acp1standard conditionsLong-pec
WT + MO1-acp1standard conditionsLong-pec
WT + MO1-acp1standard conditionsLong-pec
WT + MO1-acp1standard conditionsLong-pec
WT + MO1-acp1standard conditionsLong-pec
WT + MO1-acp1standard conditionsLong-pec
WT + MO1-acp1standard conditionsLong-pec
WT + MO1-acp1standard conditionsDay 4
WT + MO1-acp1standard conditionsDay 4
WT + MO1-acp1standard conditionsDay 5
1 - 10 of 32
Show
Mutations / Transgenics
No data available
Human Disease / Model
Human Disease Fish Conditions Evidence
chronic kidney diseaseTAS
1 - 1 of 1
Show
Sequence Targeting Reagents
Target Reagent Reagent Type
acp1MO1-acp1MRPHLNO
acp1MO2-acp1MRPHLNO
edem3MO1-edem3MRPHLNO
eya4MO3-eya4MRPHLNO
ppm1jMO1-ppm1jMRPHLNO
sos2MO1-sos2MRPHLNO
sos2MO2-sos2MRPHLNO
spegaMO1-spegaMRPHLNO
1 - 8 of 8
Show
Fish
Fish
WT
WT + MO1-acp1
WT + MO1-sos2
WT + MO2-acp1
WT + MO2-sos2
1 - 5 of 5
Show
Antibodies
Orthology
Engineered Foreign Genes
No data available
Mapping
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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.