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A catalog of genetic loci associated with kidney function from analyses of a million individuals

Matthias Wuttke, Yong Li, Man Li, Karsten B. Sieber, Mary F. Feitosa, Mathias Gorski, Adrienne Tin, Lihua Wang, Audrey Y. Chu, Anselm Hoppmann, Holger Kirsten, Ayush Giri, Jin-Fang Chai, Gardar Sveinbjornsson, Bamidele O. Tayo, Teresa Nutile, Christian Fuchsberger, Jonathan Marten, Massimiliano Cocca, Sahar Ghasemi, Yizhe Xu, Katrin Horn, Damia Noce, Peter J. Van der Most, Sanaz Sedaghat, Zhi Yu, Masato Akiyama, Saima Afaq, Tarunveer Singh Ahluwalia, Peter Almgren, Najaf Amin, Johan Arnlov, Stephan J. L. Bakker, Nisha Bansal, Daniela Baptista, Sven Bergmann, Mary L. Biggs, Ginevra Biino, Michael Boehnke, Eric Boerwinkle, Mathilde Boissel, Erwin Böttinger, Thibaud S. Boutin, Hermann Brenner, Marco Brumat, Ralph Burkhardt, Adam S. Butterworth, Eric Campana, Archie Campbell, Harry Campbell, Mickael Canouil, Robert J. Carroll, Eulalia Catamo, John C. Chambers, Miao-Ling Chee, Miao-Li Chee, Xu Chen, Ching-Yu Cheng, Yurong Cheng, Kaare Christensen, Renata Cifkova, Marina Ciullo, Maria Pina Concas, James P. Cook, Josef Coresh, Tanguy Corre, Cinzia Felicita Sala, Daniele Cusi, John Danesh, E. Warwick Daw, Martin H. De Borst, Alessandro De Grandi, Renee De Mutsert, Aiko P. J. De Vries, Frauke Degenhardt, Graciela Delgado, Ayse Demirkan, Emanuele Di Angelantonio, Katalin Dittrich, Jasmin Divers, Rajkumar Dorajoo, Kai-Uwe Eckardt, Georg Ehret, Paul Elliott, Karlhans Endlich, Michele K. Evans, Janine F. Felix, Valencia Hui Xian Foo, Oscar H. Franco, Andre Franke, Barry I. Freedman, Sandra Freitag-Wolf, Yechiel Friedlander, Philippe Froguel, Ron T. Gansevoort, He Gao, Paolo Gasparini, J. Michael Gaziano, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Franco Giulianini, Martin Gogele, Scott D. Gordon, Daniel F. Gudbjartsson, Vilmundur Gudnason, Toomas Haller, Pavel Hamet, Tamara B. Harris, Catharina A. Hartman, Caroline Hayward, Jacklyn N. Hellwege, Chew-Kiat Heng, Andrew A. Hicks, Edith Hofer, Wei Huang, Nina Hutri-Kahonen, Shih-Jen Hwang, M. Arfan Ikram, Olafur S. Indridason, Erik Ingelsson, Marcus Ising, Vincent W. V. Jaddoe, Johanna Jakobsdottir, Jost B. Jonas, Peter K. Joshi, Navya Shilpa Josyula, Bettina Jung, Mika Kahonen, Yoichiro Kamatani, Candace M. Kammerer, Masahiro Kanai, Mika Kastarinen, Shona M. Kerr, Chiea-Chuen Khor, Wieland Kiess, Marcus E. Kleber, Wolfgang Koenig, Jaspal S. Kooner, Antje Korner, Peter Kovacs, Aldi T. Kraja, Alena Krajcoviechova, Holly Kramer, Bernhard K. Kramer, Florian Kronenberg, Michiaki Kubo, Brigitte Kuhnel, Mikko Kuokkanen, Johanna Kuusisto, Martina La Bianca, Markku Laakso, Leslie A. Lange, Carl D. Langefeld, Jeannette Jen-Mai Lee, Benjamin Lehne, Terho Lehtimaki, Wolfgang Lieb, Su-Chi Lim, Lars Lind, Cecilia M. Lindgren, Jun Liu, Jianjun Liu, Markus Loeffler, Ruth J. F. Loos, Susanne Lucae, Mary Ann Lukas, Leo-Pekka Lyytikainen, Reedik Magi, Patrik K. E. Magnusson, Anubha Mahajan, Nicholas G. Martin, Jade Martins, Winfried Marz, Deborah Mascalzoni, Koichi Matsuda, Christa Meisinger, Thomas Meitinger, Olle Melander, Andres Metspalu, Evgenia K. Mikaelsdottir, Yuri Milaneschi, Kozeta Miliku, Pashupati P. Mishra, V. A. Million Veteran Program, Karen L. Mohlke, Nina Mononen, Grant W. Montgomery, Dennis O. Mook-Kanamori, Josyf C. Mychaleckyj, Girish N. Nadkarni, Mike A. Nalls, Matthias Nauck, Kjell Nikus, Boting Ning, Ilja M. Nolte, Raymond Noordam, Isleifur Olafsson, Albertine J. Oldehinkel, Marju Orho-Melander, Willem H. Ouwehand, Sandosh Padmanabhan, Nicholette D. Palmer, Runolfur Palsson, Brenda W. J. H. Penninx, Thomas Perls, Markus Perola, Mario Pirastu, Nicola Pirastu, Giorgio Pistis, Anna I. Podgornaia, Ozren Polasek, Belen Ponte, David J. Porteous, Tanja Poulain, Peter P. Pramstaller, Michael H. Preuss, Bram P. Prins, Michael A. Province, Ton J. Rabelink, Laura M. Raffield, Olli T. Raitakari, Dermot F. Reilly, Rainer Rettig, Myriam Rheinberger, Kenneth M. Rice, Paul M. Ridker, Fernando Rivadeneira, Federica Rizzi, David J. Roberts, Antonietta Robino, Peter Rossing, Igor Rudan, Rico Rueedi, Daniela Ruggiero, Kathleen A. Ryan, Yasaman Saba, Charumathi Sabanayagam, Veikko Salomaa, Erika Salvi, Kai-Uwe Saum, Helena Schmidt, Reinhold Schmidt, Ben Schottker, Christina-Alexandra Schulz, Nicole Schupf, Christian M. Shaffer, Yuan Shi, Albert V. Smith, Blair H. Smith, Nicole Soranzo, Cassandra N. Spracklen, Konstantin Strauch, Heather M. Stringham, Michael Stumvoll, Per O. Svensson, Silke Szymczak, E-Shyong Tai, Salman M. Tajuddin, Nicholas Y. Q. Tan, Kent D. Taylor, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris H. L. Thio, Hauke Thomsen, Gudmar Thorleifsson, Daniela Toniolo, Anke Tonjes, Johanne Tremblay, Ioanna Tzoulaki, Andre G. Uitterlinden, Simona Vaccargiu, Rob M. Van Dam, Pim Van der Harst, Cornelia M. Van Duijn, Digna R. Velez Edward, Niek Verweij, Suzanne Vogelezang, Uwe Volker, Peter Vollenweider, Gerard Waeber, Melanie Waldenberger, Lars Wallentin, Ya Xing Wang, Chaolong Wang, Dawn M. Waterworth, Wen Bin Wei, Harvey White, John B. Whitfield, Sarah H. Wild, James F. Wilson, Mary K. Wojczynski, Charlene Wong, Tien-Yin Wong, Liang Xu, Qiong Yang, Masayuki Yasuda, Laura M. Yerges-Armstrong, Weihua Zhang, Alan B. Zonderman, Jerome I. Rotter, Murielle Bochud, Bruce M. Psaty, Veronique Vitart, James G. Wilson, Abbas Dehghan, Afshin Parsa, Daniel I. Chasman, Kevin Ho, Andrew P. Morris, Olivier Devuyst, Shreeram Akilesh, Sarah A. Pendergrass, Xueling Sim, Carsten A. Boger, Yukinori Okada, Todd L. Edwards, Harold Snieder, Kari Stefansson, Adriana M. Hung, Iris M. Heid, Markus Scholz, Alexander Teumer, Anna Kottgen, Cristian Pattaro

  • Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes andChronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.show moreshow less

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Author details:Matthias WuttkeORCiD, Yong Li, Man LiORCiD, Karsten B. Sieber, Mary F. Feitosa, Mathias GorskiORCiD, Adrienne TinORCiD, Lihua Wang, Audrey Y. Chu, Anselm Hoppmann, Holger Kirsten, Ayush Giri, Jin-Fang Chai, Gardar Sveinbjornsson, Bamidele O. Tayo, Teresa Nutile, Christian Fuchsberger, Jonathan Marten, Massimiliano Cocca, Sahar Ghasemi, Yizhe Xu, Katrin HornORCiD, Damia Noce, Peter J. Van der Most, Sanaz Sedaghat, Zhi Yu, Masato Akiyama, Saima Afaq, Tarunveer Singh AhluwaliaORCiD, Peter Almgren, Najaf Amin, Johan ArnlovORCiD, Stephan J. L. Bakker, Nisha Bansal, Daniela Baptista, Sven Bergmann, Mary L. Biggs, Ginevra Biino, Michael Boehnke, Eric Boerwinkle, Mathilde BoisselORCiD, Erwin BöttingerGND, Thibaud S. Boutin, Hermann Brenner, Marco Brumat, Ralph BurkhardtORCiD, Adam S. Butterworth, Eric Campana, Archie Campbell, Harry CampbellORCiD, Mickael CanouilORCiD, Robert J. Carroll, Eulalia CatamoORCiD, John C. Chambers, Miao-Ling Chee, Miao-Li Chee, Xu ChenORCiD, Ching-Yu ChengORCiD, Yurong Cheng, Kaare ChristensenORCiD, Renata Cifkova, Marina CiulloORCiD, Maria Pina Concas, James P. Cook, Josef Coresh, Tanguy Corre, Cinzia Felicita Sala, Daniele Cusi, John Danesh, E. Warwick Daw, Martin H. De Borst, Alessandro De Grandi, Renee De Mutsert, Aiko P. J. De Vries, Frauke Degenhardt, Graciela Delgado, Ayse DemirkanORCiD, Emanuele Di Angelantonio, Katalin Dittrich, Jasmin Divers, Rajkumar DorajooORCiD, Kai-Uwe Eckardt, Georg Ehret, Paul Elliott, Karlhans EndlichORCiD, Michele K. Evans, Janine F. Felix, Valencia Hui Xian Foo, Oscar H. Franco, Andre Franke, Barry I. Freedman, Sandra Freitag-Wolf, Yechiel Friedlander, Philippe Froguel, Ron T. Gansevoort, He Gao, Paolo Gasparini, J. Michael Gaziano, Vilmantas Giedraitis, Christian Gieger, Giorgia GirottoORCiD, Franco Giulianini, Martin Gogele, Scott D. Gordon, Daniel F. Gudbjartsson, Vilmundur GudnasonORCiD, Toomas Haller, Pavel Hamet, Tamara B. Harris, Catharina A. Hartman, Caroline Hayward, Jacklyn N. Hellwege, Chew-Kiat Heng, Andrew A. Hicks, Edith Hofer, Wei Huang, Nina Hutri-Kahonen, Shih-Jen Hwang, M. Arfan Ikram, Olafur S. Indridason, Erik Ingelsson, Marcus Ising, Vincent W. V. Jaddoe, Johanna Jakobsdottir, Jost B. Jonas, Peter K. Joshi, Navya Shilpa JosyulaORCiD, Bettina Jung, Mika KahonenORCiD, Yoichiro Kamatani, Candace M. Kammerer, Masahiro KanaiORCiD, Mika Kastarinen, Shona M. Kerr, Chiea-Chuen Khor, Wieland Kiess, Marcus E. Kleber, Wolfgang Koenig, Jaspal S. Kooner, Antje Korner, Peter Kovacs, Aldi T. Kraja, Alena Krajcoviechova, Holly Kramer, Bernhard K. Kramer, Florian KronenbergORCiD, Michiaki Kubo, Brigitte Kuhnel, Mikko KuokkanenORCiD, Johanna Kuusisto, Martina La Bianca, Markku Laakso, Leslie A. Lange, Carl D. Langefeld, Jeannette Jen-Mai Lee, Benjamin Lehne, Terho Lehtimaki, Wolfgang Lieb, Su-Chi Lim, Lars Lind, Cecilia M. Lindgren, Jun LiuORCiD, Jianjun Liu, Markus Loeffler, Ruth J. F. Loos, Susanne Lucae, Mary Ann Lukas, Leo-Pekka Lyytikainen, Reedik Magi, Patrik K. E. Magnusson, Anubha Mahajan, Nicholas G. Martin, Jade Martins, Winfried Marz, Deborah Mascalzoni, Koichi Matsuda, Christa Meisinger, Thomas Meitinger, Olle Melander, Andres Metspalu, Evgenia K. Mikaelsdottir, Yuri Milaneschi, Kozeta Miliku, Pashupati P. Mishra, V. A. Million Veteran Program, Karen L. Mohlke, Nina Mononen, Grant W. Montgomery, Dennis O. Mook-Kanamori, Josyf C. Mychaleckyj, Girish N. Nadkarni, Mike A. Nalls, Matthias Nauck, Kjell Nikus, Boting Ning, Ilja M. Nolte, Raymond Noordam, Isleifur Olafsson, Albertine J. Oldehinkel, Marju Orho-Melander, Willem H. Ouwehand, Sandosh PadmanabhanORCiD, Nicholette D. Palmer, Runolfur Palsson, Brenda W. J. H. Penninx, Thomas Perls, Markus Perola, Mario Pirastu, Nicola PirastuORCiD, Giorgio Pistis, Anna I. Podgornaia, Ozren PolasekORCiD, Belen Ponte, David J. Porteous, Tanja Poulain, Peter P. Pramstaller, Michael H. Preuss, Bram P. Prins, Michael A. Province, Ton J. RabelinkORCiD, Laura M. Raffield, Olli T. Raitakari, Dermot F. Reilly, Rainer Rettig, Myriam Rheinberger, Kenneth M. Rice, Paul M. Ridker, Fernando RivadeneiraORCiD, Federica Rizzi, David J. Roberts, Antonietta Robino, Peter Rossing, Igor RudanORCiD, Rico Rueedi, Daniela Ruggiero, Kathleen A. Ryan, Yasaman Saba, Charumathi Sabanayagam, Veikko Salomaa, Erika SalviORCiD, Kai-Uwe Saum, Helena Schmidt, Reinhold Schmidt, Ben Schottker, Christina-Alexandra Schulz, Nicole Schupf, Christian M. Shaffer, Yuan Shi, Albert V. Smith, Blair H. Smith, Nicole Soranzo, Cassandra N. Spracklen, Konstantin Strauch, Heather M. Stringham, Michael Stumvoll, Per O. Svensson, Silke Szymczak, E-Shyong Tai, Salman M. TajuddinORCiD, Nicholas Y. Q. Tan, Kent D. Taylor, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris H. L. Thio, Hauke ThomsenORCiD, Gudmar Thorleifsson, Daniela TonioloORCiD, Anke Tonjes, Johanne Tremblay, Ioanna TzoulakiORCiD, Andre G. Uitterlinden, Simona Vaccargiu, Rob M. Van Dam, Pim Van der Harst, Cornelia M. Van Duijn, Digna R. Velez Edward, Niek VerweijORCiD, Suzanne Vogelezang, Uwe Volker, Peter Vollenweider, Gerard WaeberORCiD, Melanie Waldenberger, Lars Wallentin, Ya Xing Wang, Chaolong Wang, Dawn M. Waterworth, Wen Bin Wei, Harvey White, John B. Whitfield, Sarah H. Wild, James F. Wilson, Mary K. Wojczynski, Charlene Wong, Tien-Yin Wong, Liang Xu, Qiong Yang, Masayuki Yasuda, Laura M. Yerges-ArmstrongORCiD, Weihua Zhang, Alan B. Zonderman, Jerome I. Rotter, Murielle Bochud, Bruce M. Psaty, Veronique Vitart, James G. Wilson, Abbas Dehghan, Afshin Parsa, Daniel I. Chasman, Kevin Ho, Andrew P. Morris, Olivier Devuyst, Shreeram Akilesh, Sarah A. Pendergrass, Xueling Sim, Carsten A. Boger, Yukinori Okada, Todd L. Edwards, Harold Snieder, Kari Stefansson, Adriana M. Hung, Iris M. Heid, Markus Scholz, Alexander Teumer, Anna Kottgen, Cristian Pattaro
DOI:https://doi.org/10.1038/s41588-019-0407-x
ISSN:1061-4036
ISSN:1546-1718
Pubmed ID:https://pubmed.ncbi.nlm.nih.gov/31152163
Title of parent work (English):Nature genetics
Publisher:Nature Publ. Group
Place of publishing:New York
Publication type:Article
Language:English
Year of first publication:2019
Publication year:2019
Creating corporation:Lifelines COHort Study
Release date:2021/02/01
Volume:51
Issue:6
Number of pages:19
First page:957
Last Page:+
Funding institution:Kowa; Sanofi; National Institute on Aging (NIA)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Aging (NIA); National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA; Michael J. Fox Foundation; University of California Healthcare - Nestle Nutrition (Nestec); Metagenics; AXA; GlaxoSmithKlineGlaxoSmithKline; MSD; EisaiEisai Inc; JanssenJohnson & Johnson USAJanssen Biotech Inc; Sanofi-AventisSanofi-Aventis; Eli LillyEli Lilly; National Institute of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA; Omthera Pharmaceuticals; Pfizer New ZealandPfizer; Elsai Inc.; Dalcor Pharma UK; CSL Behring; AstraZenecaAstraZeneca; BMSBristol-Myers Squibb; Boehringer-IngelheimBoehringer Ingelheim; PfizerPfizer; Roche Diagnostics - Johnson Johnson; NovartisNovartis; Novo NordiskNovo Nordisk; Gruenenthal
Organizational units:Digital Engineering Fakultät / Hasso-Plattner-Institut für Digital Engineering GmbH
DDC classification:0 Informatik, Informationswissenschaft, allgemeine Werke / 00 Informatik, Wissen, Systeme / 000 Informatik, Informationswissenschaft, allgemeine Werke
Peer review:Referiert
Publishing method:Open Access / Green Open-Access
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