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; JE Huffman; G Tromp; C Fuchsberger; M Gorski; LP Lyytikäinen; T Nutile; S Sedaghat; R Sorice; A Tin; Q Yang; TS Ahluwalia; DE Arking; NA Bihlmeyer; CA Böger; RJ Carroll; DI Chasman; MC Cornelis; A Dehghan; JD Faul; MF Feitosa; Giovanni Gambaro; P Gasparini; F Giulianini; I Heid; J Huang; M Imboden; AU Jackson; J Jeff; MA Jhun; R Katz; A Kifley; TO Kilpeläinen; A Kumar; M Laakso; R Li-Gao; K Lohman; Y Lu; R Mägi; G Malerba; E Mihailov; KL Mohlke; DO Mook-Kanamori; A Robino; D Ruderfer; E Salvi; UM Schick; CA Schulz; AV Smith; JA Smith; M Traglia; LM Yerges-Armstrong; W Zhao; MO Goodarzi; AT Kraja; C Liu; J Wessel; CHARGE Glycemic-T2D Working Group; CHARGE Blood Pressure Working Group; E Boerwinkle; IB Borecki; J Bork-Jensen; EP Bottinger; Daniele Braga; I Brandslund; JA Brody; A Campbell; DJ Carey; C Christensen; J Coresh; E Crook; GC Curhan; D Cusi; IH de Boer; AP de Vries; JC Denny; O Devuyst; AW Dreisbach; K Endlich; T Esko; OH Franco; T Fulop; GS Gerhard; C Glümer; O Gottesman; N Grarup; V Gudnason; T Hansen; TB Harris; C Hayward; L Hocking; A Hofman; FB Hu; LL Husemoen; RD Jackson; T Jørgensen; ME Jørgensen; M Kähönen; SL Kardia; W König; C Kooperberg; J Kriebel; LJ Launer; T Lauritzen; T Lehtimäki; D Levy; P Linksted; A Linneberg; Y Liu; RJ Loos; A Lupo; C Meisinger; O Melander; A Metspalu; P Mitchell; M Nauck; P Nürnberg; M Orho-Melander; A Parsa; O Pedersen; A Peters; U Peters; O Polasek; D Porteous; NM Probst-Hensch; BM Psaty; L Qi; OT Raitakari; AP Reiner; R Rettig; PM Ridker; F Rivadeneira; JE Rossouw; F Schmidt; D Siscovick; N Soranzo; K Strauch; D Toniolo; ST Turner; AG Uitterlinden; S Ulivi; D Velayutham; U Völker; H Völzke; M Waldenberger; JJ Wang; DR Weir; D Witte; H Kuivaniemi; CS Fox; N Franceschini; W Goessling; A Köttgen; AY Chu

doi:10.1681/ASN.2016020131

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, JE Huffman, G Tromp, C Fuchsberger, M Gorski, LP Lyytikäinen, T Nutile, S Sedaghat, R Sorice, A Tin, Q Yang, TS Ahluwalia, DE Arking, NA Bihlmeyer, CA Böger, RJ CarrollDI Chasman, MC Cornelis, A Dehghan, JD Faul, MF Feitosa, Giovanni Gambaro, P Gasparini, F Giulianini, I Heid, J Huang, M Imboden, AU Jackson, J Jeff, MA Jhun, R Katz, A Kifley, TO Kilpeläinen, A Kumar, M Laakso, R Li-Gao, K Lohman, Y Lu, R Mägi, G Malerba, E Mihailov, KL Mohlke, DO Mook-Kanamori, A Robino, D Ruderfer, E Salvi, UM Schick, CA Schulz, AV Smith, JA Smith, M Traglia, LM Yerges-Armstrong, W Zhao, MO Goodarzi, AT Kraja, C Liu, J Wessel, CHARGE Glycemic-T2D Working Group, CHARGE Blood Pressure Working Group, E Boerwinkle, IB Borecki, J Bork-Jensen, EP Bottinger, Daniele Braga, I Brandslund, JA Brody, A Campbell, DJ Carey, C Christensen, J Coresh, E Crook, GC Curhan, D Cusi, IH de Boer, AP de Vries, JC Denny, O Devuyst, AW Dreisbach, K Endlich, T Esko, OH Franco, T Fulop, GS Gerhard, C Glümer, O Gottesman, N Grarup, V Gudnason, T Hansen, TB Harris, C Hayward, L Hocking, A Hofman, FB Hu, LL Husemoen, RD Jackson, T Jørgensen, ME Jørgensen, M Kähönen, SL Kardia, W König, C Kooperberg, J Kriebel, LJ Launer, T Lauritzen, T Lehtimäki, D Levy, P Linksted, A Linneberg, Y Liu, RJ Loos, A Lupo, C Meisinger, O Melander, A Metspalu, P Mitchell, M Nauck, P Nürnberg, M Orho-Melander, A Parsa, O Pedersen, A Peters, U Peters, O Polasek, D Porteous, NM Probst-Hensch, BM Psaty, L Qi, OT Raitakari, AP Reiner, R Rettig, PM Ridker, F Rivadeneira, JE Rossouw, F Schmidt, D Siscovick, N Soranzo, K Strauch, D Toniolo, ST Turner, AG Uitterlinden, S Ulivi, D Velayutham, U Völker, H Völzke, M Waldenberger, JJ Wang, DR Weir, D Witte, H Kuivaniemi, CS Fox, N Franceschini, W Goessling, A Köttgen, AY Chu

Research output: Contribution to journal › Article › peer-review

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. Copyright © 2017 by the American Society of Nephrology.

Original language	English
Pages (from-to)	981-994
Number of pages	14
Journal	Journal of the American Society of Nephrology : JASN
Volume	28
Issue number	3
DOIs	https://doi.org/10.1681/ASN.2016020131
Publication status	Published - 2017

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10.1681/ASN.2016020131

Cite this

Li, M., Li, Y., Weeks, O., Mijatovic, V., Teumer, A., Huffman, JE., Tromp, G., Fuchsberger, C., Gorski, M., Lyytikäinen, LP., Nutile, T., Sedaghat, S., Sorice, R., Tin, A., Yang, Q., Ahluwalia, TS., Arking, DE., Bihlmeyer, NA., Böger, CA., ... Chu, AY. (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. https://doi.org/10.1681/ASN.2016020131

SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. / Li, M; Li, Y; Weeks, O; Mijatovic, V; Teumer, A; Huffman, JE; Tromp, G; Fuchsberger, C; Gorski, M; Lyytikäinen, LP; Nutile, T; Sedaghat, S; Sorice, R; Tin, A; Yang, Q; Ahluwalia, TS; Arking, DE; Bihlmeyer, NA; Böger, CA; Carroll, RJ; Chasman, DI; Cornelis, MC; Dehghan, A; Faul, JD; Feitosa, MF; Gambaro, Giovanni; Gasparini, P; Giulianini, F; Heid, I; Huang, J; Imboden, M; Jackson, AU; Jeff, J; Jhun, MA; Katz, R; Kifley, A; Kilpeläinen, TO; Kumar, A; Laakso, M; Li-Gao, R; Lohman, K; Lu, Y; Mägi, 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, C; Wessel, J; Group, CHARGE Glycemic-T2D Working; Group, CHARGE Blood Pressure Working; Boerwinkle, E; Borecki, IB; Bork-Jensen, J; Bottinger, EP; Braga, Daniele; Brandslund, I; Brody, JA; Campbell, A; Carey, DJ; Christensen, C; Coresh, J; Crook, E; Curhan, GC; Cusi, D; de Boer, IH; de Vries, AP; Denny, JC; Devuyst, O; Dreisbach, AW; Endlich, K; Esko, T; Franco, OH; Fulop, T; Gerhard, GS; Glümer, C; Gottesman, O; Grarup, N; Gudnason, V; Hansen, T; Harris, TB; Hayward, C; Hocking, L; Hofman, A; Hu, FB; Husemoen, LL; Jackson, RD; Jørgensen, T; Jørgensen, ME; Kähönen, M; Kardia, SL; König, W; Kooperberg, C; Kriebel, J; Launer, LJ; Lauritzen, T; Lehtimäki, T; Levy, D; Linksted, P; Linneberg, A; Liu, Y; Loos, RJ; 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, 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; Völker, U; Völzke, H; Waldenberger, M; Wang, JJ; Weir, DR; Witte, D; Kuivaniemi, H; Fox, CS; Franceschini, N; Goessling, W; Köttgen, A; Chu, AY.

In: Journal of the American Society of Nephrology : JASN, Vol. 28, No. 3, 2017, p. 981-994.

Research output: Contribution to journal › Article › peer-review

Li, M, Li, Y, Weeks, O, Mijatovic, V, Teumer, A, Huffman, JE, Tromp, G, Fuchsberger, C, Gorski, M, Lyytikäinen, LP, Nutile, T, Sedaghat, S, Sorice, R, Tin, A, Yang, Q, Ahluwalia, TS, Arking, DE, Bihlmeyer, NA, Böger, CA, Carroll, RJ, Chasman, DI, Cornelis, MC, Dehghan, A, Faul, JD, Feitosa, MF, Gambaro, G, Gasparini, P, Giulianini, F, Heid, I, Huang, J, Imboden, M, Jackson, AU, Jeff, J, Jhun, MA, Katz, R, Kifley, A, Kilpeläinen, TO, Kumar, A, Laakso, M, Li-Gao, R, Lohman, K, Lu, Y, Mägi, 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, C, Wessel, J, Group, CHARGEG-TDW, Group, CHARGEBPW, 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, AP, Denny, JC, Devuyst, O, Dreisbach, AW, Endlich, K, Esko, T, Franco, OH, Fulop, T, Gerhard, GS, Glümer, C, Gottesman, O, Grarup, N, Gudnason, V, Hansen, T, Harris, TB, Hayward, C, Hocking, L, Hofman, A, Hu, FB, Husemoen, LL, Jackson, RD, Jørgensen, T, Jørgensen, ME, Kähönen, M, Kardia, SL, König, W, Kooperberg, C, Kriebel, J, Launer, LJ, Lauritzen, T, Lehtimäki, T, Levy, D, Linksted, P, Linneberg, A, Liu, Y, Loos, RJ, 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, 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, Völker, U, Völzke, H, Waldenberger, M, Wang, JJ, Weir, DR, Witte, D, Kuivaniemi, H, Fox, CS, Franceschini, N, Goessling, W, Köttgen, A & Chu, AY 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, vol. 28, no. 3, pp. 981-994. https://doi.org/10.1681/ASN.2016020131

Li, M ; Li, Y ; Weeks, O ; Mijatovic, V ; Teumer, A ; Huffman, JE ; Tromp, G ; Fuchsberger, C ; Gorski, M ; Lyytikäinen, LP ; Nutile, T ; Sedaghat, S ; Sorice, R ; Tin, A ; Yang, Q ; Ahluwalia, TS ; Arking, DE ; Bihlmeyer, NA ; Böger, CA ; Carroll, RJ ; Chasman, DI ; Cornelis, MC ; Dehghan, A ; Faul, JD ; Feitosa, MF ; Gambaro, Giovanni ; Gasparini, P ; Giulianini, F ; Heid, I ; Huang, J ; Imboden, M ; Jackson, AU ; Jeff, J ; Jhun, MA ; Katz, R ; Kifley, A ; Kilpeläinen, TO ; Kumar, A ; Laakso, M ; Li-Gao, R ; Lohman, K ; Lu, Y ; Mägi, 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, C ; Wessel, J ; Group, CHARGE Glycemic-T2D Working ; Group, CHARGE Blood Pressure Working ; Boerwinkle, E ; Borecki, IB ; Bork-Jensen, J ; Bottinger, EP ; Braga, Daniele ; Brandslund, I ; Brody, JA ; Campbell, A ; Carey, DJ ; Christensen, C ; Coresh, J ; Crook, E ; Curhan, GC ; Cusi, D ; de Boer, IH ; de Vries, AP ; Denny, JC ; Devuyst, O ; Dreisbach, AW ; Endlich, K ; Esko, T ; Franco, OH ; Fulop, T ; Gerhard, GS ; Glümer, C ; Gottesman, O ; Grarup, N ; Gudnason, V ; Hansen, T ; Harris, TB ; Hayward, C ; Hocking, L ; Hofman, A ; Hu, FB ; Husemoen, LL ; Jackson, RD ; Jørgensen, T ; Jørgensen, ME ; Kähönen, M ; Kardia, SL ; König, W ; Kooperberg, C ; Kriebel, J ; Launer, LJ ; Lauritzen, T ; Lehtimäki, T ; Levy, D ; Linksted, P ; Linneberg, A ; Liu, Y ; Loos, RJ ; 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, 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 ; Völker, U ; Völzke, H ; Waldenberger, M ; Wang, JJ ; Weir, DR ; Witte, D ; Kuivaniemi, H ; Fox, CS ; Franceschini, N ; Goessling, W ; Köttgen, A ; Chu, AY. / SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. In: Journal of the American Society of Nephrology : JASN. 2017 ; Vol. 28, No. 3. pp. 981-994.

@article{8fb64b87016e4eee8def15b3c9766bf9,

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

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. Copyright {\textcopyright} 2017 by the American Society of Nephrology.",

author = "M Li and Y Li and O Weeks and V Mijatovic and A Teumer and JE Huffman and G Tromp and C Fuchsberger and M Gorski and LP Lyytik{\"a}inen and T Nutile and S Sedaghat and R Sorice and A Tin and Q Yang and TS Ahluwalia and DE Arking and NA Bihlmeyer and CA B{\"o}ger and RJ Carroll and DI Chasman and MC Cornelis and A Dehghan and JD Faul and MF Feitosa and Giovanni Gambaro and P Gasparini and F Giulianini and I Heid and J Huang and M Imboden and AU Jackson and J Jeff and MA Jhun and R Katz and A Kifley and TO Kilpel{\"a}inen and A Kumar and M Laakso and R Li-Gao and K Lohman and Y Lu and R M{\"a}gi and G Malerba and E Mihailov and KL Mohlke and DO Mook-Kanamori and A Robino and D Ruderfer and E Salvi and UM Schick and CA Schulz and AV Smith and JA Smith and M Traglia and LM Yerges-Armstrong and W Zhao and MO Goodarzi and AT Kraja and C Liu and J Wessel and Group, {CHARGE Glycemic-T2D Working} and Group, {CHARGE Blood Pressure Working} and E Boerwinkle and IB Borecki and J Bork-Jensen and EP Bottinger and Daniele Braga and I Brandslund and JA Brody and A Campbell and DJ Carey and C Christensen and J Coresh and E Crook and GC Curhan and D Cusi and {de Boer}, IH and {de Vries}, AP and JC Denny and O Devuyst and AW Dreisbach and K Endlich and T Esko and OH Franco and T Fulop and GS Gerhard and C Gl{\"u}mer and O Gottesman and N Grarup and V Gudnason and T Hansen and TB Harris and C Hayward and L Hocking and A Hofman and FB Hu and LL Husemoen and RD Jackson and T J{\o}rgensen and ME J{\o}rgensen and M K{\"a}h{\"o}nen and SL Kardia and W K{\"o}nig and C Kooperberg and J Kriebel and LJ Launer and T Lauritzen and T Lehtim{\"a}ki and D Levy and P Linksted and A Linneberg and Y Liu and RJ Loos and A Lupo and C Meisinger and O Melander and A Metspalu and P Mitchell and M Nauck and P N{\"u}rnberg and M Orho-Melander and A Parsa and O Pedersen and A Peters and U Peters and O Polasek and D Porteous and NM Probst-Hensch and BM Psaty and L Qi and OT Raitakari and AP Reiner and R Rettig and PM Ridker and F Rivadeneira and JE Rossouw and F Schmidt and D Siscovick and N Soranzo and K Strauch and D Toniolo and ST Turner and AG Uitterlinden and S Ulivi and D Velayutham and U V{\"o}lker and H V{\"o}lzke and M Waldenberger and JJ Wang and DR Weir and D Witte and H Kuivaniemi and CS Fox and N Franceschini and W Goessling and A K{\"o}ttgen and AY Chu",

year = "2017",

doi = "10.1681/ASN.2016020131",

language = "English",

volume = "28",

pages = "981--994",

journal = "Journal of the American Society of Nephrology : JASN",

issn = "1046-6673",

publisher = "American Society of Nephrology",

number = "3",

}

TY - JOUR

T1 - SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function

AU - Li, M

AU - Li, Y

AU - Weeks, O

AU - Mijatovic, V

AU - Teumer, A

AU - Huffman, JE

AU - Tromp, G

AU - Fuchsberger, C

AU - Gorski, M

AU - Lyytikäinen, LP

AU - Nutile, T

AU - Sedaghat, S

AU - Sorice, R

AU - Tin, A

AU - Yang, Q

AU - Ahluwalia, TS

AU - Arking, DE

AU - Bihlmeyer, NA

AU - Böger, CA

AU - Carroll, RJ

AU - Chasman, DI

AU - Cornelis, MC

AU - Dehghan, A

AU - Faul, JD

AU - Feitosa, MF

AU - Gambaro, Giovanni

AU - Gasparini, P

AU - Giulianini, F

AU - Heid, I

AU - Huang, J

AU - Imboden, M

AU - Jackson, AU

AU - Jeff, J

AU - Jhun, MA

AU - Katz, R

AU - Kifley, A

AU - Kilpeläinen, TO

AU - Kumar, A

AU - Laakso, M

AU - Li-Gao, R

AU - Lohman, K

AU - Lu, Y

AU - Mägi, R

AU - Malerba, G

AU - Mihailov, E

AU - Mohlke, KL

AU - Mook-Kanamori, DO

AU - Robino, A

AU - Ruderfer, D

AU - Salvi, E

AU - Schick, UM

AU - Schulz, CA

AU - Smith, AV

AU - Smith, JA

AU - Traglia, M

AU - Yerges-Armstrong, LM

AU - Zhao, W

AU - Goodarzi, MO

AU - Kraja, AT

AU - Liu, C

AU - Wessel, J

AU - Group, CHARGE Glycemic-T2D Working

AU - Group, CHARGE Blood Pressure Working

AU - Boerwinkle, E

AU - Borecki, IB

AU - Bork-Jensen, J

AU - Bottinger, EP

AU - Braga, Daniele

AU - Brandslund, I

AU - Brody, JA

AU - Campbell, A

AU - Carey, DJ

AU - Christensen, C

AU - Coresh, J

AU - Crook, E

AU - Curhan, GC

AU - Cusi, D

AU - de Boer, IH

AU - de Vries, AP

AU - Denny, JC

AU - Devuyst, O

AU - Dreisbach, AW

AU - Endlich, K

AU - Esko, T

AU - Franco, OH

AU - Fulop, T

AU - Gerhard, GS

AU - Glümer, C

AU - Gottesman, O

AU - Grarup, N

AU - Gudnason, V

AU - Hansen, T

AU - Harris, TB

AU - Hayward, C

AU - Hocking, L

AU - Hofman, A

AU - Hu, FB

AU - Husemoen, LL

AU - Jackson, RD

AU - Jørgensen, T

AU - Jørgensen, ME

AU - Kähönen, M

AU - Kardia, SL

AU - König, W

AU - Kooperberg, C

AU - Kriebel, J

AU - Launer, LJ

AU - Lauritzen, T

AU - Lehtimäki, T

AU - Levy, D

AU - Linksted, P

AU - Linneberg, A

AU - Liu, Y

AU - Loos, RJ

AU - Lupo, A

AU - Meisinger, C

AU - Melander, O

AU - Metspalu, A

AU - Mitchell, P

AU - Nauck, M

AU - Nürnberg, P

AU - Orho-Melander, M

AU - Parsa, A

AU - Pedersen, O

AU - Peters, A

AU - Peters, U

AU - Polasek, O

AU - Porteous, D

AU - Probst-Hensch, NM

AU - Psaty, BM

AU - Qi, L

AU - Raitakari, OT

AU - Reiner, AP

AU - Rettig, R

AU - Ridker, PM

AU - Rivadeneira, F

AU - Rossouw, JE

AU - Schmidt, F

AU - Siscovick, D

AU - Soranzo, N

AU - Strauch, K

AU - Toniolo, D

AU - Turner, ST

AU - Uitterlinden, AG

AU - Ulivi, S

AU - Velayutham, D

AU - Völker, U

AU - Völzke, H

AU - Waldenberger, M

AU - Wang, JJ

AU - Weir, DR

AU - Witte, D

AU - Kuivaniemi, H

AU - Fox, CS

AU - Franceschini, N

AU - Goessling, W

AU - Köttgen, A

AU - Chu, AY

PY - 2017

Y1 - 2017

N2 - 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. Copyright © 2017 by the American Society of Nephrology.

AB - 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. Copyright © 2017 by the American Society of Nephrology.

U2 - 10.1681/ASN.2016020131

DO - 10.1681/ASN.2016020131

M3 - Article

VL - 28

SP - 981

EP - 994

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

SN - 1046-6673

IS - 3

ER -

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

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