Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies.
Link: https://doi.org/S0085-2538(22)00454-9
Authors: Gorski, Mathias; Rasheed, Humaira; Teumer, Alexander; Thomas, Laurent F; Graham, Sarah E; Sveinbjornsson, Gardar; Winkler, Thomas W; Günther, Felix; Stark, Klaus J; Chai, Jin-Fang; Tayo, Bamidele O; Wuttke, Matthias; Li, Yong; Tin, Adrienne; Ahluwalia, Tarunveer S; Ärnlöv, Johan; Åsvold, Bjørn Olav; Bakker, Stephan J L; Banas, Bernhard; Bansal, Nisha; Biggs, Mary L; Biino, Ginevra; Böhnke, 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-Kähönen, Nina; Hveem, Kristian; Hwang, Shih-Jen; Ikram, M Arfan; Josyula, Navya Shilpa; Jung, Bettina; Kähönen, Mika; Karabegović, Irma; Khor, Chiea-Chuen; Koenig, Wolfgang; Kramer, Holly; Krämer, Bernhard K; Kühnel, Brigitte; Kuusisto, Johanna; Laakso, Markku; Lange, Leslie A; Lehtimäki, Terho; Li, Man; Lieb, Wolfgang; , ; Lind, Lars; Lindgren, Cecilia M; Loos, Ruth J F; Lukas, Mary Ann; Lyytikäinen, 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; Schöttker, 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; Völker, Uwe; Wakai, Kenji; Waldenberger, Melanie; Wallentin, Lars; 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; Böger, Carsten A; Pattaro, Cristian; Köttgen, Anna; Kronenberg, Florian; Heid, Iris M
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 genome-wide 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 age-dependency 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.