학술논문
Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies
Document Type
Author
Gorski, Mathias; Rasheed, Humaira; Teumer, Alexander; Thomas, Laurent F.; Graham, Sarah E.; Sveinbjornsson, Gardar; Winkler, Thomas W.; Guenther, Felix; Stark, Klaus J.; Chai, Jin-Fang; Tayo, Bamidele O.; Wuttke, Matthias; Li, Yong; Tin, Adrienne; Ahluwalia, Tarunveer S.; Ärnlöv, Johan; Asvold, Bjorn Olav; Bakker, Stephan J. L.; Banas, Bernhard; Bansal, Nisha; Biggs, Mary L.; Biino, Ginevra; Bohnke, Michael; Boerwinkle, Eric; Bottinger, Erwin P.; Brenner, Hermann; Brumpton, Ben; Carroll, Robert J.; Chaker, Layal; Chalmers, John; Chee, Miao-Li; Chee, Miao-Ling; Cheng, Ching-Yu; Chu, Audrey Y.; Ciullo, Marina; Cocca, Massimiliano; Cook, James P.; Coresh, Josef; Cusi, Daniele; de Borst, Martin H.; Degenhardt, Frauke; Eckardt, Kai-Uwe; Endlich, Karlhans; Evans, Michele K.; Feitosa, Mary F.; Franke, Andre; Freitag-Wolf, Sandra; Fuchsberger, Christian; Gampawar, Piyush; Gansevoort, Ron T.; Ghanbari, Mohsen; Ghasemi, Sahar; Giedraitis, Vilmantas; Gieger, Christian; Gudbjartsson, Daniel F.; Hallan, Stein; Hamet, Pavel; Hishida, Asahi; Ho, Kevin; Hofer, Edith; Holleczek, Bernd; Holm, Hilma; Hoppmann, Anselm; Horn, Katrin; Hutri-Kahonen, Nina; Hveem, Kristian; Hwang, Shih-Jen; Ikram, M. Arfan; Josyula, Navya Shilpa; Jung, Bettina; Kahonen, Mika; Karabegovic, Irma; Khor, Chiea-Chuen; Koenig, Wolfgang; Kramer, Holly; Kramer, Bernhard K.; Kuehnel, Brigitte; Kuusisto, Johanna; Laakso, Markku; Lange, Leslie A.; Lehtimaki, Terho; Li, Man; Lieb, Wolfgang; Lind, Lars; Lindgren, Cecilia M.; Loos, Ruth J. F.; Lukas, Mary Ann; Lyytikainen, Leo-Pekka; Mahajan, Anubha; Matias-Garcia, Pamela R.; Meisinger, Christa; Meitinger, Thomas; Melander, Olle; Milaneschi, Yuri; Mishra, Pashupati P.; Mononen, Nina; Morris, Andrew P.; Mychaleckyj, Josyf C.; Nadkarni, Girish N.; Naito, Mariko; Nakatochi, Masahiro; Nalls, Mike A.; Nauck, Matthias; Nikus, Kjell; Ning, Boting; Nolte, Ilja M.; Nutile, Teresa; O'Donoghue, Michelle L.; O'Connell, Jeffrey; Olafsson, Isleifur; Orho-Melander, Marju; Parsa, Afshin; Pendergrass, Sarah A.; Penninx, Brenda W. J. H.; Pirastu, Mario; Preuss, Michael H.; Psaty, Bruce M.; Raffield, Laura M.; Raitakari, Olli T.; Rheinberger, Myriam; Rice, Kenneth M.; Rizzi, Federica; Rosenkranz, Alexander R.; Rossing, Peter; Rotter, Jerome I.; Ruggiero, Daniela; Ryan, Kathleen A.; Sabanayagam, Charumathi; Salvi, Erika; Schmidt, Helena; Schmidt, Reinhold; Scholz, Markus; Schoettker, Ben; Schulz, Christina-Alexandra; Sedaghat, Sanaz; Shaffer, Christian M.; Sieber, Karsten B.; Sim, Xueling; Sims, Mario; Snieder, Harold; Stanzick, Kira J.; Thorsteinsdottir, Unnur; Stocker, Hannah; Strauch, Konstantin; Stringham, Heather M.; Sulem, Patrick; Szymczak, Silke; Taylor, Kent D.; Thio, Chris H. L.; Tremblay, Johanne; Vaccargiu, Simona; van der Harst, Pim; van der Most, Peter J.; Verweij, Niek; Volker, Uwe; Wakai, Kenji; Waldenberger, Melanie; Wallentin, Lars, 1943; Wallner, Stefan; Wang, Judy; Waterworth, Dawn M.; White, Harvey D.; Willer, Cristen J.; Wong, Tien-Yin; Woodward, Mark; Yang, Qiong; Yerges-Armstrong, Laura M.; Zimmermann, Martina; Zonderman, Alan B.; Bergler, Tobias; Stefansson, Kari; Boger, Carsten A.; Pattaro, Cristian; Koettgen, Anna; Kronenberg, Florian; Heid, Iris M.
Source
Kidney International. 102(3):624-639
Subject
Language
English
ISSN
0085-2538
Abstract
Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genomewide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR- baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant- by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with agedependency of genetic cross- section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in- silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03- 1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.