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

Teumer, Alexander; Li, Yong; Ghasemi, Sahar; Prins, Bram P.; Wuttke, Matthias; Hermle, Tobias; Giri, Ayush; Sieber, Karsten B.; Qiu, Chengxiang and Kirsten, Holger, et al. (2019) In Nature Communications 10(1).
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... (More)

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.

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Nature Communications
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10
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Nature Publishing Group
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  • scopus:85072119437
ISSN
2041-1723
DOI
10.1038/s41467-019-11576-0
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English
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9b03d4f3-aae0-43d2-8f9e-eab00a7e05db
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2019-09-19 11:29:36
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2019-11-08 11:45:36
@article{9b03d4f3-aae0-43d2-8f9e-eab00a7e05db,
  abstract     = {<p>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.</p>},
  author       = {Teumer, Alexander and Li, Yong and Ghasemi, Sahar and Prins, Bram P. and Wuttke, Matthias and Hermle, Tobias and Giri, Ayush and Sieber, Karsten B. and Qiu, Chengxiang and Kirsten, Holger and Tin, Adrienne and Chu, Audrey Y. and Bansal, Nisha and Feitosa, Mary F. and Wang, Lihua and Chai, Jin Fang and Cocca, Massimiliano and Fuchsberger, Christian and Gorski, Mathias and Hoppmann, Anselm and Horn, Katrin and Li, Man and Marten, Jonathan and Noce, Damia and Nutile, Teresa and Sedaghat, Sanaz and Sveinbjornsson, Gardar and Tayo, Bamidele O. and van der Most, Peter J. and Xu, Yizhe and Yu, Zhi and Gerstner, Lea and Ärnlöv, Johan and Bakker, Stephan J.L. and Baptista, Daniela and Biggs, Mary L. and Boerwinkle, Eric and Brenner, Hermann and Burkhardt, Ralph and Carroll, Robert J. and Chee, Miao Li and Chee, Miao Ling and Chen, Mengmeng and Cheng, Ching Yu and Cook, James P. and Coresh, Josef and Corre, Tanguy and Danesh, John and de Borst, Martin H. and De Grandi, Alessandro and de Mutsert, Renée and de Vries, Aiko P.J. and Degenhardt, Frauke and Dittrich, Katalin and Divers, Jasmin and Eckardt, Kai Uwe and Ehret, Georg and Endlich, Karlhans and Felix, Janine F. and Franco, Oscar H. and Franke, Andre and Freedman, Barry I. and Freitag-Wolf, Sandra and Gansevoort, Ron T. and Giedraitis, Vilmantas and Gögele, Martin and Grundner-Culemann, Franziska and Gudbjartsson, Daniel F. and Gudnason, Vilmundur and Hamet, Pavel and Harris, Tamara B. and Hicks, Andrew A. and Holm, Hilma and Foo, Valencia Hui Xian and Hwang, Shih Jen and Ikram, M. Arfan and Ingelsson, Erik and Jaddoe, Vincent W.V. and Jakobsdottir, Johanna and Josyula, Navya Shilpa and Jung, Bettina and Kähönen, Mika and Khor, Chiea Chuen and Kiess, Wieland and Koenig, Wolfgang and Körner, Antje and Kovacs, Peter and Kramer, Holly and Krämer, Bernhard K. and Kronenberg, Florian and Lange, Leslie A. and Langefeld, Carl D. and Lee, Jeannette Jen Mai and Lehtimäki, Terho and Lieb, Wolfgang and Lim, Su Chi and Lind, Lars and Lindgren, Cecilia M. and Liu, Jianjun and Loeffler, Markus and Lyytikäinen, Leo Pekka and Mahajan, Anubha and Maranville, Joseph C. and Mascalzoni, Deborah and McMullen, Barbara and Meisinger, Christa and Meitinger, Thomas and Miliku, Kozeta and Mook-Kanamori, Dennis O. and Müller-Nurasyid, Martina and Mychaleckyj, Josyf C. and Nauck, Matthias and Nikus, Kjell and Ning, Boting and Noordam, Raymond and Connell, Jeffrey O. and Olafsson, Isleifur and Palmer, Nicholette D. and Peters, Annette and Podgornaia, Anna I. and Ponte, Belen and Poulain, Tanja and Pramstaller, Peter P. and Rabelink, Ton J. and Raffield, Laura M. and Reilly, Dermot F. and Rettig, Rainer and Rheinberger, Myriam and Rice, Kenneth M. and Rivadeneira, Fernando and Runz, Heiko and Ryan, Kathleen A. and Sabanayagam, Charumathi and Saum, Kai Uwe and Schöttker, Ben and Shaffer, Christian M. and Shi, Yuan and Smith, Albert V. and Strauch, Konstantin and Stumvoll, Michael and Sun, Benjamin B. and Szymczak, Silke and Tai, E. Shyong and Tan, Nicholas Y.Q. and Taylor, Kent D. and Teren, Andrej and Tham, Yih Chung and Thiery, Joachim and Thio, Chris H.L. and Thomsen, Hauke and Thorsteinsdottir, Unnur and Tönjes, Anke and Tremblay, Johanne and Uitterlinden, André G. and van der Harst, Pim and Verweij, Niek and Vogelezang, Suzanne and Völker, Uwe and Waldenberger, Melanie and Wang, Chaolong and Wilson, Otis D. and Wong, Charlene and Wong, Tien Yin and Yang, Qiong and Yasuda, Masayuki and Akilesh, Shreeram and Bochud, Murielle and Böger, Carsten A. and Devuyst, Olivier and Edwards, Todd L. and Ho, Kevin and Morris, Andrew P. and Parsa, Afshin and Pendergrass, Sarah A. and Psaty, Bruce M. and Rotter, Jerome I. and Stefansson, Kari and Wilson, James G. and Susztak, Katalin and Snieder, Harold and Heid, Iris M. and Scholz, Markus and Butterworth, Adam S. and Hung, Adriana M. and Pattaro, Cristian and Köttgen, Anna},
  issn         = {2041-1723},
  language     = {eng},
  month        = {09},
  number       = {1},
  pages        = {1},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria},
  url          = {http://dx.doi.org/10.1038/s41467-019-11576-0},
  volume       = {10},
  year         = {2019},
}