Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
Mathias Gorski, Bettina Jung, Yong Li, Pamela Matias-Garcia, Matthias Wuttke, Stefan Coassin, Chris Thio, Marcus Kleber, Thomas Winkler, Veronika Wanner, Jin-Fang Chai, Audrey Chu, Massimiliano Cocca, Mary Feitosa, Sahar Ghasemi, Anselm Hoppmann, Katrin Horn, Man Li, Teresa Nutile, Markus Scholz, Karsten Sieber, Alexander Teumer, Adrienne Tin, Judy Wang, Bamidele Tayo, Tarunveer Ahluwalia, Peter Almgren, Stephan Bakker, Bernhard Banas, Nisha Bansal, Mary Biggs, Eric Boerwinkle, Erwin Bottinger, Hermann Brenner, Robert Carroll, John Chalmers, Miao-Li Chee, Miao-Ling Chee, Ching-Yu Cheng, Josef Coresh, Martin Borst, Frauke Degenhardt, Kai-Uwe Eckardt, Karlhans Endlich, Andre Franke, Sandra Freitag-Wolf, Piyush Gampawar, Ron Gansevoort, Mohsen Ghanbari, Christian Gieger, Pavel Hamet, Kevin Ho, Edith Hofer, Bernd Holleczek, Valencia Xian Foo, Nina Hutri-Kähönen, Shih-Jen Hwang, M. Ikram, Navya Josyula, Mika Kähönen, Chiea-Chuen Khor, Wolfgang Koenig, Holly Kramer, Bernhard Krämer, Brigitte Kühnel, Leslie Lange, Terho Lehtimäki, Wolfgang Lieb, Ruth Loos, Mary Lukas, Leo-Pekka Lyytikäinen, Christa Meisinger, Thomas Meitinger, Olle Melander, Yuri Milaneschi, Pashupati Mishra, Nina Mononen, Josyf Mychaleckyj, Girish Nadkarni, Matthias Nauck, Kjell Nikus, Boting Ning, Ilja Nolte, Michelle O'Donoghue, Marju Orho-Melander, Sarah Pendergrass, Brenda Penninx, Michael Preuss, Bruce Psaty, Laura Raffield, Olli Raitakari, Rainer Rettig, Myriam Rheinberger, Kenneth Rice, Alexander Rosenkranz, Peter Rossing, Jerome Rotter, Charumathi Sabanayagam, Helena Schmidt, Reinhold Schmidt, Ben Schöttker, Christina-Alexandra Schulz, Sanaz Sedaghat, Christian Shaffer, Konstantin Strauch, Silke Szymczak, Kent Taylor, Johanne Tremblay, Layal Chaker, van der Harst, Pim, Peter van der Most, Niek Verweij, Uwe Völker, Melanie Waldenberger, Lars Wallentin, Dawn Waterworth, Harvey White, James Wilson, Tien-Yin Wong, Mark Woodward, Qiong Yang, Masayuki Yasuda, Laura Yerges-Armstrong, Yan Zhang, Harold Snieder, Christoph Wanner, Carsten Böger, Anna Köttgen, Florian Kronenberg, Cristian Pattaro, Iris Heid
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more („Rapid3“; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline („CKDi25“; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.