Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Alexander Teumer; Yong Li; Sahar Ghasemi; Bram P. Prins; Matthias Wuttke; Tobias Hermle; Ayush Giri; Karsten B. Sieber; Chengxiang Qiu; Holger Kirsten; Adrienne Tin; Audrey Y. Chu; Nisha Bansal; Mary F. Feitosa; Lihua Wang; Jin Fang Chai; Massimiliano Cocca; Christian Fuchsberger; Mathias Gorski; Anselm Hoppmann; Katrin Horn; Man Li; Jonathan Marten; Damia Noce; Teresa Nutile; Sanaz Sedaghat; Gardar Sveinbjornsson; Bamidele O. Tayo; Peter J. van der Most; Yizhe Xu; Zhi Yu; Lea Gerstner; Johan Ärnlöv; Stephan J.L. Bakker; Daniela Baptista; Mary L. Biggs; Eric Boerwinkle; Hermann Brenner; Ralph Burkhardt; Robert J. Carroll; Miao Li Chee; Miao Ling Chee; Mengmeng Chen; Ching Yu Cheng; James P. Cook; Josef Coresh; Tanguy Corre; John Danesh; Martin H. de Borst; Alessandro De Grandi; Renée de Mutsert; Aiko P.J. de Vries; Frauke Degenhardt; Katalin Dittrich; Jasmin Divers; Kai Uwe Eckardt; Georg Ehret; Karlhans Endlich; Janine F. Felix; Oscar H. Franco; Andre Franke; Barry I. Freedman; Sandra Freitag-Wolf; Ron T. Gansevoort; Vilmantas Giedraitis; Martin Gögele; Franziska Grundner-Culemann; Daniel F. Gudbjartsson; Vilmundur Gudnason; Pavel Hamet; Tamara B. Harris; Andrew A. Hicks; Hilma Holm; Valencia Hui Xian Foo; Shih Jen Hwang; M. Arfan Ikram; Erik Ingelsson; Vincent W.V. Jaddoe; Johanna Jakobsdottir; Navya Shilpa Josyula; Bettina Jung; Mika Kähönen; Chiea Chuen Khor; Wieland Kiess; Wolfgang Koenig; Antje Körner; Peter Kovacs; Holly Kramer; Bernhard K. Krämer; Florian Kronenberg; Leslie A. Lange; Carl D. Langefeld; Jeannette Jen Mai Lee; Terho Lehtimäki; Wolfgang Lieb; Su Chi Lim; Lars Lind; Cecilia M. Lindgren; Jianjun Liu; Markus Loeffler; Leo Pekka Lyytikäinen; Anubha Mahajan; Joseph C. Maranville; Deborah Mascalzoni; Barbara McMullen; Christa Meisinger; Thomas Meitinger; Kozeta Miliku; Dennis O. Mook-Kanamori; Martina Müller-Nurasyid; Josyf C. Mychaleckyj; Matthias Nauck; Kjell Nikus; Boting Ning; Raymond Noordam; Jeffrey O’ Connell; Isleifur Olafsson; Nicholette D. Palmer; Annette Peters; Anna I. Podgornaia; Belen Ponte; Tanja Poulain; Peter P. Pramstaller; Ton J. Rabelink; Laura M. Raffield; Dermot F. Reilly; Rainer Rettig; Myriam Rheinberger; Kenneth M. Rice; Fernando Rivadeneira; Heiko Runz; Kathleen A. Ryan; Charumathi Sabanayagam; Kai Uwe Saum; Ben Schöttker; Christian M. Shaffer; Yuan Shi; Albert V. Smith; Konstantin Strauch; Michael Stumvoll; Benjamin B. Sun; Silke Szymczak; E. Shyong Tai; Nicholas Y.Q. Tan; Kent D. Taylor; Andrej Teren; Yih Chung Tham; Joachim Thiery; Chris H.L. Thio; Hauke Thomsen; Unnur Thorsteinsdottir; Anke Tönjes; Johanne Tremblay; André G. Uitterlinden; Pim van der Harst; Niek Verweij; Suzanne Vogelezang; Uwe Völker; Melanie Waldenberger; Chaolong Wang; Otis D. Wilson; Charlene Wong; Tien Yin Wong; Qiong Yang; Masayuki Yasuda; Shreeram Akilesh; Murielle Bochud; Carsten A. Böger; Olivier Devuyst; Todd L. Edwards; Kevin Ho; Andrew P. Morris; Afshin Parsa; Sarah A. Pendergrass; Bruce M. Psaty; Jerome I. Rotter; Kari Stefansson; James G. Wilson; Katalin Susztak; Harold Snieder; Iris M. Heid; Markus Scholz; Adam S. Butterworth; Adriana M. Hung; Cristian Pattaro; Anna Köttgen

doi:10.1038/s41467-019-11576-0

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Alexander Teumer, Yong Li, Sahar Ghasemi, Bram P. Prins, Matthias Wuttke, Tobias Hermle, Ayush Giri, Karsten B. Sieber, Chengxiang Qiu, Holger Kirsten, Adrienne Tin, Audrey Y. Chu, Nisha Bansal, Mary F. Feitosa, Lihua Wang, Jin Fang Chai, Massimiliano Cocca, Christian Fuchsberger, Mathias Gorski, Anselm HoppmannKatrin Horn, Man Li, Jonathan Marten, Damia Noce, Teresa Nutile, Sanaz Sedaghat, Gardar Sveinbjornsson, Bamidele O. Tayo, Peter J. van der Most, Yizhe Xu, Zhi Yu, Lea Gerstner, Johan Ärnlöv, Stephan J.L. Bakker, Daniela Baptista, Mary L. Biggs, Eric Boerwinkle, Hermann Brenner, Ralph Burkhardt, Robert J. Carroll, Miao Li Chee, Miao Ling Chee, Mengmeng Chen, Ching Yu Cheng, James P. Cook, Josef Coresh, Tanguy Corre, John Danesh, Martin H. de Borst, Alessandro De Grandi, Renée de Mutsert, Aiko P.J. de Vries, Frauke Degenhardt, Katalin Dittrich, Jasmin Divers, Kai Uwe Eckardt, Georg Ehret, Karlhans Endlich, Janine F. Felix, Oscar H. Franco, Andre Franke, Barry I. Freedman, Sandra Freitag-Wolf, Ron T. Gansevoort, Vilmantas Giedraitis, Martin Gögele, Franziska Grundner-Culemann, Daniel F. Gudbjartsson, Vilmundur Gudnason, Pavel Hamet, Tamara B. Harris, Andrew A. Hicks, Hilma Holm, Valencia Hui Xian Foo, Shih Jen Hwang, M. Arfan Ikram, Erik Ingelsson, Vincent W.V. Jaddoe, Johanna Jakobsdottir, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Chiea Chuen Khor, Wieland Kiess, Wolfgang Koenig, Antje Körner, Peter Kovacs, Holly Kramer, Bernhard K. Krämer, Florian Kronenberg, Leslie A. Lange, Carl D. Langefeld, Jeannette Jen Mai Lee, Terho Lehtimäki, Wolfgang Lieb, Su Chi Lim, Lars Lind, Cecilia M. Lindgren, Jianjun Liu, Markus Loeffler, Leo Pekka Lyytikäinen, Anubha Mahajan, Joseph C. Maranville, Deborah Mascalzoni, Barbara McMullen, Christa Meisinger, Thomas Meitinger, Kozeta Miliku, Dennis O. Mook-Kanamori, Martina Müller-Nurasyid, Josyf C. Mychaleckyj, Matthias Nauck, Kjell Nikus, Boting Ning, Raymond Noordam, Jeffrey O’ Connell, Isleifur Olafsson, Nicholette D. Palmer, Annette Peters, Anna I. Podgornaia, Belen Ponte, Tanja Poulain, Peter P. Pramstaller, Ton J. Rabelink, Laura M. Raffield, Dermot F. Reilly, Rainer Rettig, Myriam Rheinberger, Kenneth M. Rice, Fernando Rivadeneira, Heiko Runz, Kathleen A. Ryan, Charumathi Sabanayagam, Kai Uwe Saum, Ben Schöttker, Christian M. Shaffer, Yuan Shi, Albert V. Smith, Konstantin Strauch, Michael Stumvoll, Benjamin B. Sun, Silke Szymczak, E. Shyong Tai, Nicholas Y.Q. Tan, Kent D. Taylor, Andrej Teren, Yih Chung Tham, Joachim Thiery, Chris H.L. Thio, Hauke Thomsen, Unnur Thorsteinsdottir, Anke Tönjes, Johanne Tremblay, André G. Uitterlinden, Pim van der Harst, Niek Verweij, Suzanne Vogelezang, Uwe Völker, Melanie Waldenberger, Chaolong Wang, Otis D. Wilson, Charlene Wong, Tien Yin Wong, Qiong Yang, Masayuki Yasuda, Shreeram Akilesh, Murielle Bochud, Carsten A. Böger, Olivier Devuyst, Todd L. Edwards, Kevin Ho, Andrew P. Morris, Afshin Parsa, Sarah A. Pendergrass, Bruce M. Psaty, Jerome I. Rotter, Kari Stefansson, James G. Wilson, Katalin Susztak, Harold Snieder, Iris M. Heid, Markus Scholz, Adam S. Butterworth, Adriana M. Hung, Cristian Pattaro, Anna Köttgen

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

127 Scopus citations

Abstract

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

Original language	English (US)
Article number	4130
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-11576-0
State	Published - Dec 1 2019
Externally published	Yes

Bibliographical note

Funding Information:
Competing interests: Karsten B. Sieber is full-time employee of GlaxoSmithKline. Gardar Sveinbjornsson, Daniel F. Gudbjartsson, Hilma Holm, Unnur Thorsteinsdottir and Kari Stefansson are full-time employees of deCODE genetics, Amgen Inc. John Danesh is member of the Novartis Cardiovascular and Metabolic Advisory Board, received grant support from Novartis. Oscar H. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. Wolfgang Koenig received modest consultation fees for advisory board meetings from Amgen, DalCor, Kowa, Novartis, Pfizer and Sanofi, and modest personal fees for lectures from Amgen, AstraZeneca, Novartis, Pfizer and Sanofi. Anna I. Podgornaia and Dermot F. Reilly are employees of Merck Sharp Dohme Corp., Whitehouse Station, NJ, USA. Kevin Ho disclosed a research and financial relationship with Sanofi-Genzyme. Bruce M. Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Markus Scholz: Consultancy of and grant support from Merck Serono not related to this project. Adam S. Butterworth received grants from MSD, Pfizer, Novartis, Biogen and Bioverativ and personal fees from Novartis. Anna Köttgen received grant support from Gruenenthal not related to this project. The other authors declare no competing interests.

Publisher Copyright:
© 2019, The Author(s).

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-019-11576-0

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Teumer, A., Li, Y., Ghasemi, S., Prins, B. P., Wuttke, M., Hermle, T., Giri, A., Sieber, K. B., Qiu, C., Kirsten, H., Tin, A., Chu, A. Y., Bansal, N., Feitosa, M. F., Wang, L., Chai, J. F., Cocca, M., Fuchsberger, C., Gorski, M., ... Köttgen, A. (2019). Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria. Nature communications, 10(1), Article 4130. https://doi.org/10.1038/s41467-019-11576-0

Teumer, A, Li, Y, Ghasemi, S, Prins, BP, Wuttke, M, Hermle, T, Giri, A, Sieber, KB, Qiu, C, Kirsten, H, Tin, A, Chu, AY, Bansal, N, Feitosa, MF, Wang, L, Chai, JF, Cocca, M, Fuchsberger, C, Gorski, M, Hoppmann, A, Horn, K, Li, M, Marten, J, Noce, D, Nutile, T, Sedaghat, S, Sveinbjornsson, G, Tayo, BO, van der Most, PJ, Xu, Y, Yu, Z, Gerstner, L, Ärnlöv, J, Bakker, SJL, Baptista, D, Biggs, ML, Boerwinkle, E, Brenner, H, Burkhardt, R, Carroll, RJ, Chee, ML, Chee, ML, Chen, M, Cheng, CY, Cook, JP, Coresh, J, Corre, T, Danesh, J, de Borst, MH, De Grandi, A, de Mutsert, R, de Vries, APJ, Degenhardt, F, Dittrich, K, Divers, J, Eckardt, KU, Ehret, G, Endlich, K, Felix, JF, Franco, OH, Franke, A, Freedman, BI, Freitag-Wolf, S, Gansevoort, RT, Giedraitis, V, Gögele, M, Grundner-Culemann, F, Gudbjartsson, DF, Gudnason, V, Hamet, P, Harris, TB, Hicks, AA, Holm, H, Foo, VHX, Hwang, SJ, Ikram, MA, Ingelsson, E, Jaddoe, VWV, Jakobsdottir, J, Josyula, NS, Jung, B, Kähönen, M, Khor, CC, Kiess, W, Koenig, W, Körner, A, Kovacs, P, Kramer, H, Krämer, BK, Kronenberg, F, Lange, LA, Langefeld, CD, Lee, JJM, Lehtimäki, T, Lieb, W, Lim, SC, Lind, L, Lindgren, CM, Liu, J, Loeffler, M, Lyytikäinen, LP, Mahajan, A, Maranville, JC, Mascalzoni, D, McMullen, B, Meisinger, C, Meitinger, T, Miliku, K, Mook-Kanamori, DO, Müller-Nurasyid, M, Mychaleckyj, JC, Nauck, M, Nikus, K, Ning, B, Noordam, R, Connell, JO, Olafsson, I, Palmer, ND, Peters, A, Podgornaia, AI, Ponte, B, Poulain, T, Pramstaller, PP, Rabelink, TJ, Raffield, LM, Reilly, DF, Rettig, R, Rheinberger, M, Rice, KM, Rivadeneira, F, Runz, H, Ryan, KA, Sabanayagam, C, Saum, KU, Schöttker, B, Shaffer, CM, Shi, Y, Smith, AV, Strauch, K, Stumvoll, M, Sun, BB, Szymczak, S, Tai, ES, Tan, NYQ, Taylor, KD, Teren, A, Tham, YC, Thiery, J, Thio, CHL, Thomsen, H, Thorsteinsdottir, U, Tönjes, A, Tremblay, J, Uitterlinden, AG, van der Harst, P, Verweij, N, Vogelezang, S, Völker, U, Waldenberger, M, Wang, C, Wilson, OD, Wong, C, Wong, TY, Yang, Q, Yasuda, M, Akilesh, S, Bochud, M, Böger, CA, Devuyst, O, Edwards, TL, Ho, K, Morris, AP, Parsa, A, Pendergrass, SA, Psaty, BM, Rotter, JI, Stefansson, K, Wilson, JG, Susztak, K, Snieder, H, Heid, IM, Scholz, M, Butterworth, AS, Hung, AM, Pattaro, C & Köttgen, A 2019, 'Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria', Nature communications, vol. 10, no. 1, 4130. https://doi.org/10.1038/s41467-019-11576-0

@article{01ea0b1aee7e4a2bb242f0e949968b86,

title = "Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria",

abstract = "Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.",

author = "Alexander Teumer and Yong Li and Sahar Ghasemi and Prins, {Bram P.} and Matthias Wuttke and Tobias Hermle and Ayush Giri and Sieber, {Karsten B.} and Chengxiang Qiu and Holger Kirsten and Adrienne Tin and Chu, {Audrey Y.} and Nisha Bansal and Feitosa, {Mary F.} and Lihua Wang and Chai, {Jin Fang} and Massimiliano Cocca and Christian Fuchsberger and Mathias Gorski and Anselm Hoppmann and Katrin Horn and Man Li and Jonathan Marten and Damia Noce and Teresa Nutile and Sanaz Sedaghat and Gardar Sveinbjornsson and Tayo, {Bamidele O.} and {van der Most}, {Peter J.} and Yizhe Xu and Zhi Yu and Lea Gerstner and Johan {\"A}rnl{\"o}v and Bakker, {Stephan J.L.} and Daniela Baptista and Biggs, {Mary L.} and Eric Boerwinkle and Hermann Brenner and Ralph Burkhardt and Carroll, {Robert J.} and Chee, {Miao Li} and Chee, {Miao Ling} and Mengmeng Chen and Cheng, {Ching Yu} and Cook, {James P.} and Josef Coresh and Tanguy Corre and John Danesh and {de Borst}, {Martin H.} and {De Grandi}, Alessandro and {de Mutsert}, Ren{\'e}e and {de Vries}, {Aiko P.J.} and Frauke Degenhardt and Katalin Dittrich and Jasmin Divers and Eckardt, {Kai Uwe} and Georg Ehret and Karlhans Endlich and Felix, {Janine F.} and Franco, {Oscar H.} and Andre Franke and Freedman, {Barry I.} and Sandra Freitag-Wolf and Gansevoort, {Ron T.} and Vilmantas Giedraitis and Martin G{\"o}gele and Franziska Grundner-Culemann and Gudbjartsson, {Daniel F.} and Vilmundur Gudnason and Pavel Hamet and Harris, {Tamara B.} and Hicks, {Andrew A.} and Hilma Holm and Foo, {Valencia Hui Xian} and Hwang, {Shih Jen} and Ikram, {M. Arfan} and Erik Ingelsson and Jaddoe, {Vincent W.V.} and Johanna Jakobsdottir and Josyula, {Navya Shilpa} and Bettina Jung and Mika K{\"a}h{\"o}nen and Khor, {Chiea Chuen} and Wieland Kiess and Wolfgang Koenig and Antje K{\"o}rner and Peter Kovacs and Holly Kramer and Kr{\"a}mer, {Bernhard K.} and Florian Kronenberg and Lange, {Leslie A.} and Langefeld, {Carl D.} and Lee, {Jeannette Jen Mai} and Terho Lehtim{\"a}ki and Wolfgang Lieb and Lim, {Su Chi} and Lars Lind and Lindgren, {Cecilia M.} and Jianjun Liu and Markus Loeffler and Lyytik{\"a}inen, {Leo Pekka} and Anubha Mahajan and Maranville, {Joseph C.} and Deborah Mascalzoni and Barbara McMullen and Christa Meisinger and Thomas Meitinger and Kozeta Miliku and Mook-Kanamori, {Dennis O.} and Martina M{\"u}ller-Nurasyid and Mychaleckyj, {Josyf C.} and Matthias Nauck and Kjell Nikus and Boting Ning and Raymond Noordam and Connell, {Jeffrey O{\textquoteright}} and Isleifur Olafsson and Palmer, {Nicholette D.} and Annette Peters and Podgornaia, {Anna I.} and Belen Ponte and Tanja Poulain and Pramstaller, {Peter P.} and Rabelink, {Ton J.} and Raffield, {Laura M.} and Reilly, {Dermot F.} and Rainer Rettig and Myriam Rheinberger and Rice, {Kenneth M.} and Fernando Rivadeneira and Heiko Runz and Ryan, {Kathleen A.} and Charumathi Sabanayagam and Saum, {Kai Uwe} and Ben Sch{\"o}ttker and Shaffer, {Christian M.} and Yuan Shi and Smith, {Albert V.} and Konstantin Strauch and Michael Stumvoll and Sun, {Benjamin B.} and Silke Szymczak and Tai, {E. Shyong} and Tan, {Nicholas Y.Q.} and Taylor, {Kent D.} and Andrej Teren and Tham, {Yih Chung} and Joachim Thiery and Thio, {Chris H.L.} and Hauke Thomsen and Unnur Thorsteinsdottir and Anke T{\"o}njes and Johanne Tremblay and Uitterlinden, {Andr{\'e} G.} and {van der Harst}, Pim and Niek Verweij and Suzanne Vogelezang and Uwe V{\"o}lker and Melanie Waldenberger and Chaolong Wang and Wilson, {Otis D.} and Charlene Wong and Wong, {Tien Yin} and Qiong Yang and Masayuki Yasuda and Shreeram Akilesh and Murielle Bochud and B{\"o}ger, {Carsten A.} and Olivier Devuyst and Edwards, {Todd L.} and Kevin Ho and Morris, {Andrew P.} and Afshin Parsa and Pendergrass, {Sarah A.} and Psaty, {Bruce M.} and Rotter, {Jerome I.} and Kari Stefansson and Wilson, {James G.} and Katalin Susztak and Harold Snieder and Heid, {Iris M.} and Markus Scholz and Butterworth, {Adam S.} and Hung, {Adriana M.} and Cristian Pattaro and Anna K{\"o}ttgen",

note = "Funding Information: Competing interests: Karsten B. Sieber is full-time employee of GlaxoSmithKline. Gardar Sveinbjornsson, Daniel F. Gudbjartsson, Hilma Holm, Unnur Thorsteinsdottir and Kari Stefansson are full-time employees of deCODE genetics, Amgen Inc. John Danesh is member of the Novartis Cardiovascular and Metabolic Advisory Board, received grant support from Novartis. Oscar H. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestl{\'e} Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. Wolfgang Koenig received modest consultation fees for advisory board meetings from Amgen, DalCor, Kowa, Novartis, Pfizer and Sanofi, and modest personal fees for lectures from Amgen, AstraZeneca, Novartis, Pfizer and Sanofi. Anna I. Podgornaia and Dermot F. Reilly are employees of Merck Sharp Dohme Corp., Whitehouse Station, NJ, USA. Kevin Ho disclosed a research and financial relationship with Sanofi-Genzyme. Bruce M. Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Markus Scholz: Consultancy of and grant support from Merck Serono not related to this project. Adam S. Butterworth received grants from MSD, Pfizer, Novartis, Biogen and Bioverativ and personal fees from Novartis. Anna K{\"o}ttgen received grant support from Gruenenthal not related to this project. The other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-11576-0",

language = "English (US)",

volume = "10",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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TY - JOUR

T1 - Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

AU - Teumer, Alexander

AU - Li, Yong

AU - Ghasemi, Sahar

AU - Prins, Bram P.

AU - Wuttke, Matthias

AU - Hermle, Tobias

AU - Giri, Ayush

AU - Sieber, Karsten B.

AU - Qiu, Chengxiang

AU - Kirsten, Holger

AU - Tin, Adrienne

AU - Chu, Audrey Y.

AU - Bansal, Nisha

AU - Feitosa, Mary F.

AU - Wang, Lihua

AU - Chai, Jin Fang

AU - Cocca, Massimiliano

AU - Fuchsberger, Christian

AU - Gorski, Mathias

AU - Hoppmann, Anselm

AU - Horn, Katrin

AU - Li, Man

AU - Marten, Jonathan

AU - Noce, Damia

AU - Nutile, Teresa

AU - Sedaghat, Sanaz

AU - Sveinbjornsson, Gardar

AU - Tayo, Bamidele O.

AU - van der Most, Peter J.

AU - Xu, Yizhe

AU - Yu, Zhi

AU - Gerstner, Lea

AU - Ärnlöv, Johan

AU - Bakker, Stephan J.L.

AU - Baptista, Daniela

AU - Biggs, Mary L.

AU - Boerwinkle, Eric

AU - Brenner, Hermann

AU - Burkhardt, Ralph

AU - Carroll, Robert J.

AU - Chee, Miao Li

AU - Chee, Miao Ling

AU - Chen, Mengmeng

AU - Cheng, Ching Yu

AU - Cook, James P.

AU - Coresh, Josef

AU - Corre, Tanguy

AU - Danesh, John

AU - de Borst, Martin H.

AU - De Grandi, Alessandro

AU - de Mutsert, Renée

AU - de Vries, Aiko P.J.

AU - Degenhardt, Frauke

AU - Dittrich, Katalin

AU - Divers, Jasmin

AU - Eckardt, Kai Uwe

AU - Ehret, Georg

AU - Endlich, Karlhans

AU - Felix, Janine F.

AU - Franco, Oscar H.

AU - Franke, Andre

AU - Freedman, Barry I.

AU - Freitag-Wolf, Sandra

AU - Gansevoort, Ron T.

AU - Giedraitis, Vilmantas

AU - Gögele, Martin

AU - Grundner-Culemann, Franziska

AU - Gudbjartsson, Daniel F.

AU - Gudnason, Vilmundur

AU - Hamet, Pavel

AU - Harris, Tamara B.

AU - Hicks, Andrew A.

AU - Holm, Hilma

AU - Foo, Valencia Hui Xian

AU - Hwang, Shih Jen

AU - Ikram, M. Arfan

AU - Ingelsson, Erik

AU - Jaddoe, Vincent W.V.

AU - Jakobsdottir, Johanna

AU - Josyula, Navya Shilpa

AU - Jung, Bettina

AU - Kähönen, Mika

AU - Khor, Chiea Chuen

AU - Kiess, Wieland

AU - Koenig, Wolfgang

AU - Körner, Antje

AU - Kovacs, Peter

AU - Kramer, Holly

AU - Krämer, Bernhard K.

AU - Kronenberg, Florian

AU - Lange, Leslie A.

AU - Langefeld, Carl D.

AU - Lee, Jeannette Jen Mai

AU - Lehtimäki, Terho

AU - Lieb, Wolfgang

AU - Lim, Su Chi

AU - Lind, Lars

AU - Lindgren, Cecilia M.

AU - Liu, Jianjun

AU - Loeffler, Markus

AU - Lyytikäinen, Leo Pekka

AU - Mahajan, Anubha

AU - Maranville, Joseph C.

AU - Mascalzoni, Deborah

AU - McMullen, Barbara

AU - Meisinger, Christa

AU - Meitinger, Thomas

AU - Miliku, Kozeta

AU - Mook-Kanamori, Dennis O.

AU - Müller-Nurasyid, Martina

AU - Mychaleckyj, Josyf C.

AU - Nauck, Matthias

AU - Nikus, Kjell

AU - Ning, Boting

AU - Noordam, Raymond

AU - Connell, Jeffrey O’

AU - Olafsson, Isleifur

AU - Palmer, Nicholette D.

AU - Peters, Annette

AU - Podgornaia, Anna I.

AU - Ponte, Belen

AU - Poulain, Tanja

AU - Pramstaller, Peter P.

AU - Rabelink, Ton J.

AU - Raffield, Laura M.

AU - Reilly, Dermot F.

AU - Rettig, Rainer

AU - Rheinberger, Myriam

AU - Rice, Kenneth M.

AU - Rivadeneira, Fernando

AU - Runz, Heiko

AU - Ryan, Kathleen A.

AU - Sabanayagam, Charumathi

AU - Saum, Kai Uwe

AU - Schöttker, Ben

AU - Shaffer, Christian M.

AU - Shi, Yuan

AU - Smith, Albert V.

AU - Strauch, Konstantin

AU - Stumvoll, Michael

AU - Sun, Benjamin B.

AU - Szymczak, Silke

AU - Tai, E. Shyong

AU - Tan, Nicholas Y.Q.

AU - Taylor, Kent D.

AU - Teren, Andrej

AU - Tham, Yih Chung

AU - Thiery, Joachim

AU - Thio, Chris H.L.

AU - Thomsen, Hauke

AU - Thorsteinsdottir, Unnur

AU - Tönjes, Anke

AU - Tremblay, Johanne

AU - Uitterlinden, André G.

AU - van der Harst, Pim

AU - Verweij, Niek

AU - Vogelezang, Suzanne

AU - Völker, Uwe

AU - Waldenberger, Melanie

AU - Wang, Chaolong

AU - Wilson, Otis D.

AU - Wong, Charlene

AU - Wong, Tien Yin

AU - Yang, Qiong

AU - Yasuda, Masayuki

AU - Akilesh, Shreeram

AU - Bochud, Murielle

AU - Böger, Carsten A.

AU - Devuyst, Olivier

AU - Edwards, Todd L.

AU - Ho, Kevin

AU - Morris, Andrew P.

AU - Parsa, Afshin

AU - Pendergrass, Sarah A.

AU - Psaty, Bruce M.

AU - Rotter, Jerome I.

AU - Stefansson, Kari

AU - Wilson, James G.

AU - Susztak, Katalin

AU - Snieder, Harold

AU - Heid, Iris M.

AU - Scholz, Markus

AU - Butterworth, Adam S.

AU - Hung, Adriana M.

AU - Pattaro, Cristian

AU - Köttgen, Anna

N1 - Funding Information: Competing interests: Karsten B. Sieber is full-time employee of GlaxoSmithKline. Gardar Sveinbjornsson, Daniel F. Gudbjartsson, Hilma Holm, Unnur Thorsteinsdottir and Kari Stefansson are full-time employees of deCODE genetics, Amgen Inc. John Danesh is member of the Novartis Cardiovascular and Metabolic Advisory Board, received grant support from Novartis. Oscar H. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. Wolfgang Koenig received modest consultation fees for advisory board meetings from Amgen, DalCor, Kowa, Novartis, Pfizer and Sanofi, and modest personal fees for lectures from Amgen, AstraZeneca, Novartis, Pfizer and Sanofi. Anna I. Podgornaia and Dermot F. Reilly are employees of Merck Sharp Dohme Corp., Whitehouse Station, NJ, USA. Kevin Ho disclosed a research and financial relationship with Sanofi-Genzyme. Bruce M. Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Markus Scholz: Consultancy of and grant support from Merck Serono not related to this project. Adam S. Butterworth received grants from MSD, Pfizer, Novartis, Biogen and Bioverativ and personal fees from Novartis. Anna Köttgen received grant support from Gruenenthal not related to this project. The other authors declare no competing interests. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

AB - Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

UR - http://www.scopus.com/inward/record.url?scp=85072119437&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072119437&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-11576-0

DO - 10.1038/s41467-019-11576-0

M3 - Article

C2 - 31511532

AN - SCOPUS:85072119437

SN - 2041-1723

VL - 10

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 4130

ER -

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

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