Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
Authors: Teumer Alexander , Li Yong , Ghasemi Sahar , Prins Bram P. , Wuttke Matthias , Hermle Tobias , Giri Ayush , Sieber Karsten B. , Qiu Chengxiang , Kirsten Holger , Tin Adrienne , Chu Audrey Y. , Bansal Nisha , Feitosa Mary F. , Wang Lihua , Chai Jin-Fang , Cocca Massimiliano , Fuchsberger Christian , Gorski Mathias , Hoppmann Anselm , Horn Katrin , Li Man , Marten Jonathan , Noce Damia , Nutile Teresa , Sedaghat Sanaz , Sveinbjornsson Gardar , Tayo Bamidele O. , van der Most Peter J. , Xu Yizhe , Yu Zhi , Gerstner Lea , Ärnlöv Johan , Bakker Stephan J. L. , Baptista Daniela , Biggs Mary L. , Boerwinkle Eric , Brenner Hermann , Burkhardt Ralph , Carroll Robert J. , Chee Miao-Li , Chee Miao-Ling , Chen Mengmeng , Cheng Ching-Yu , Cook James P. , Coresh Josef , Corre Tanguy , Danesh John , de Borst Martin H. , De Grandi Alessandro , de Mutsert Renée , de Vries Aiko P. J. , Degenhardt Frauke , Dittrich Katalin , Divers Jasmin , Eckardt Kai-Uwe , Ehret Georg , Endlich Karlhans , Felix Janine F. , Franco Oscar H. , Franke Andre , Freedman Barry I. , Freitag-Wolf Sandra , Gansevoort Ron T. , Giedraitis Vilmantas , Gögele Martin , Grundner-Culemann Franziska , Gudbjartsson Daniel F. , Gudnason Vilmundur , Hamet Pavel , Harris Tamara B. , Hicks Andrew A. , Holm Hilma , Foo Valencia Hui Xian , Hwang Shih-Jen , Ikram M. Arfan , Ingelsson Erik , Jaddoe Vincent W. V. , Jakobsdottir Johanna , Josyula Navya Shilpa , Jung Bettina , Kähönen Mika , Khor Chiea-Chuen , Kiess Wieland , Koenig Wolfgang , Körner Antje , Kovacs Peter , Kramer Holly , Krämer Bernhard K. , Kronenberg Florian , Lange Leslie A. , Langefeld Carl D. , Lee Jeannette Jen-Mai , Lehtimäki Terho , Lieb Wolfgang , Lim Su-Chi , Lind Lars , Lindgren Cecilia M. , Liu Jianjun , Loeffler Markus , Lyytikäinen Leo-Pekka , Mahajan Anubha , Maranville Joseph C. , Mascalzoni Deborah , McMullen Barbara , Meisinger Christa , Meitinger Thomas , Miliku Kozeta , Mook-Kanamori Dennis O. , Müller-Nurasyid Martina , Mychaleckyj Josyf C. , Nauck Matthias , Nikus Kjell , Ning Boting , Noordam Raymond , Connell Jeffrey O’ , Olafsson Isleifur , Palmer Nicholette D. , Peters Annette , Podgornaia Anna I. , Ponte Belen , Poulain Tanja , Pramstaller Peter P. , Rabelink Ton J. , Raffield Laura M. , Reilly Dermot F. , Rettig Rainer , Rheinberger Myriam , Rice Kenneth M. , Rivadeneira Fernando , Runz Heiko , Ryan Kathleen A. , Sabanayagam Charumathi , Saum Kai-Uwe , Schöttker Ben , Shaffer Christian M. , Shi Yuan , Smith Albert V. , Strauch Konstantin , Stumvoll Michael , Sun Benjamin B. , Szymczak Silke , Tai E-Shyong , Tan Nicholas Y. Q. , Taylor Kent D. , Teren Andrej , Tham Yih-Chung , Thiery Joachim , Thio Chris H. L. , Thomsen Hauke , Thorsteinsdottir Unnur , Tönjes Anke , Tremblay Johanne , Uitterlinden André G. , van der Harst Pim , Verweij Niek , Vogelezang Suzanne , Völker Uwe , Waldenberger Melanie , Wang Chaolong , Wilson Otis D. , Wong Charlene , Wong Tien-Yin , Yang Qiong , Yasuda Masayuki , Akilesh Shreeram , Bochud Murielle , Böger Carsten A. , Devuyst Olivier , Edwards Todd L. , Ho Kevin , Morris Andrew P. , Parsa Afshin , Pendergrass Sarah A. , Psaty Bruce M. , Rotter Jerome I. , Stefansson Kari , Wilson James G. , Susztak Katalin , Snieder Harold , Heid Iris M. , Scholz Markus , Butterworth Adam S. , Hung Adriana M. , Pattaro Cristian , Köttgen Anna 
Published: September 2019

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.