Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
Autoren
Alexander Teumer, Yong Li, Sahar Ghasemi, Bram Prins, Matthias Wuttke, Tobias Hermle, Ayush Giri, Karsten Sieber, Chengxiang Qiu, Holger Kirsten, Adrienne Tin, Audrey Chu, Nisha Bansal, Mary 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 Tayo, Peter van der Most, Yizhe Xu, Zhi Yu, Lea Gerstner, Johan Arnlov, Stephan Bakker, Daniela Baptista, Mary Biggs, Eric Boerwinkle, Hermann Brenner, Ralph Burkhardt, Robert Carroll, Miao-Li Chee, Miao-Ling Chee, Mengmeng Chen, Ching-Yu Cheng, James Cook, Josef Coresh, Tanguy Corre, John Danesh, Martin Borst, Alessandro Grandi, Renee Mutsert, Aiko Vries, Frauke Degenhardt, Katalin Dittrich, Jasmin Divers, Kai-Uwe Eckardt, Georg Ehret, Karlhans Endlich, Janine Felix, Oscar Franco, Andre Franke, Barry Freedman, Sandra Freitag-Wolf, Ron Gansevoort, Vilmantas Giedraitis, Martin Gogele, Franziska Grundner-Culemann, Daniel Gudbjartsson, Vilmundur Gudnason, Pavel Hamet, Tamara Harris, Andrew Hicks, Hilma Holm, Valencia Foo, Shih-Jen Hwang, M. Ikram, Erik Ingelsson, Vincent Jaddoe, Johanna Jakobsdottir, Navya Josyula, Bettina Jung, Mika Kahonen, Chiea-Chuen Khor, Wieland Kiess, Wolfgang Koenig, Antje Korner, Peter Kovacs, Holly Kramer, Bernhard Kramer, Florian Kronenberg, Leslie Lange, Carl Langefeld, Jeannette Lee, Terho Lehtimaki, Wolfgang Lieb, Su-Chi Lim, Lars Lind, Cecilia Lindgren, Jianjun Liu, Markus Loeffler, Leo-Pekka Lyytikainen, Anubha Mahajan, Joseph Maranville, Deborah Mascalzoni, Barbara McMullen, Christa Meisinger, Thomas Meitinger, Kozeta Miliku, Dennis Mook-Kanamori, Martina Muller-Nurasyid, Josyf Mychaleckyj, Matthias Nauck, Kjell Nikus, Boting Ning, Raymond Noordam, Jeffrey Connell, Isleifur Olafsson, Nicholette Palmer, Annette Peters, Anna Podgornaia, Belen Ponte, Tanja Poulain, Peter Pramstaller, Ton Rabelink, Laura Raffield, Dermot Reilly, Rainer Rettig, Myriam Rheinberger, Kenneth Rice, Fernando Rivadeneira, Heiko Runz, Kathleen Ryan, Charumathi Sabanayagam, Kai-Uwe Saum, Ben Schottker, Christian Shaffer, Yuan Shi, Albert Smith, Konstantin Strauch, Michael Stumvoll, Benjamin Sun, Silke Szymczak, E-Shyong Tai, Nicholas Tan, Kent Taylor, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris Thio, Hauke Thomsen, Unnur Thorsteinsdottir, Anke Tonjes, Johanne Tremblay, Andre Uitterlinden, van der Harst, Pim, Niek Verweij, Suzanne Vogelezang, Uwe Volker, Melanie Waldenberger, Chaolong Wang, Otis Wilson, Charlene Wong, Tien-Yin Wong, Qiong Yang, Masayuki Yasuda, Shreeram Akilesh, Murielle Bochud, Carsten Boger, Olivier Devuyst, Todd Edwards, Kevin Ho, Andrew Morris, Afshin Parsa, Sarah Pendergrass, Bruce Psaty, Jerome Rotter, Kari Stefansson, James Wilson, Katalin Susztak, Harold Snieder, Iris Heid, Markus Scholz, Adam Butterworth, Adriana Hung, Cristian Pattaro, Anna Kottgen
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.