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 | |
State | Published - Dec 1 2019 |
ASJC Scopus subject areas
- Physics and Astronomy(all)
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
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In: Nature communications, Vol. 10, No. 1, 4130, 01.12.2019.
Research output: Contribution to journal › Article › peer-review
}
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 -