Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies
Creators: name: Gorski, Mathias
name: Rasheed, Humaira
name: Teumer, Alexander
name: Thomas, Laurent F.
name: Graham, Sarah E.
name: Sveinbjornsson, Gardar
name: Winkler, Thomas W.
name: Günther, Felix
name: Stark, Klaus J.
name: Chai, Jin-Fang
name: Tayo, Bamidele O.
name: Wuttke, Matthias
name: Li, Yong
name: Tin, Adrienne
name: Ahluwalia, Tarunveer S.
name: Ärnlöv, Johan
name: Åsvold, Bjørn Olav
name: Bakker, Stephan J. L.
name: Banas, Bernhard
name: Bansal, Nisha
name: Biggs, Mary L.
name: Biino, Ginevra
name: Böhnke, Michael
name: Boerwinkle, Eric
name: Bottinger, Erwin P.
name: Brenner, Hermann
name: Brumpton, Ben
name: Carroll, Robert J.
name: Chaker, Layal
name: Chalmers, John
name: Chee, Miao-Li
name: Chee, Miao-Ling
name: Cheng, Ching-Yu
name: Chu, Audrey Y.
name: Ciullo, Marina
name: Cocca, Massimiliano
name: Cook, James P.
name: Coresh, Josef
name: Cusi, Daniele
name: de Borst, Martin H.
name: Degenhardt, Frauke
name: Eckardt, Kai-Uwe
name: Endlich, Karlhans
name: Evans, Michele K.
name: Feitosa, Mary F.
name: Franke, Andre
name: Freitag-Wolf, Sandra
name: Fuchsberger, Christian
name: Gampawar, Piyush
name: Gansevoort, Ron T.
name: Ghanbari, Mohsen
name: Ghasemi, Sahar
name: Giedraitis, Vilmantas
name: Gieger, Christian
name: Gudbjartsson, Daniel F.
name: Hallan, Stein
name: Hamet, Pavel
name: Hishida, Asahi
name: Ho, Kevin
name: Hofer, Edith
name: Holleczek, Bernd
name: Holm, Hilma
name: Hoppmann, Anselm
name: Horn, Katrin
name: Hutri-Kähönen, Nina
name: Hveem, Kristian
name: Hwang, Shih-Jen
name: Ikram, M. Arfan
name: Josyula, Navya Shilpa
name: Jung, Bettina
name: Kähönen, Mika
name: Karabegović, Irma
name: Khor, Chiea-Chuen
name: Koenig, Wolfgang
name: Kramer, Holly
name: Krämer, Bernhard K.
name: Kühnel, Brigitte
name: Kuusisto, Johanna
name: Laakso, Markku
name: Lange, Leslie A.
name: Lehtimäki, Terho
name: Li, Man
name: Lieb, Wolfgang
name: Lind, Lars
name: Lindgren, Cecilia M.
name: Loos, Ruth J. F.
name: Lukas, Mary Ann
name: Lyytikäinen, Leo-Pekka
name: Mahajan, Anubha
name: Matias-Garcia, Pamela R.
name: Meisinger, Christa
name: Meitinger, Thomas
name: Melander, Olle
name: Milaneschi, Yuri
name: Mishra, Pashupati P.
name: Mononen, Nina
name: Morris, Andrew P.
name: Mychaleckyj, Josyf C.
name: Nadkarni, Girish N.
name: Naito, Mariko
name: Nakatochi, Masahiro
name: Nalls, Mike A.
name: Nauck, Matthias
name: Nikus, Kjell
name: Ning, Boting
name: Nolte, Ilja M.
name: Nutile, Teresa
name: O’Donoghue, Michelle L.
name: O'Connell, Jeffrey R.
name: Olafsson, Isleifur
name: Orho-Melander, Marju
name: Parsa, Afshin
name: Pendergrass, Sarah A.
name: Penninx, Brenda W. J. H.
name: Pirastu, Mario
name: Preuss, Michael H.
name: Psaty, Bruce M.
name: Raffield, Laura M.
name: Raitakari, Olli T.
name: Rheinberger, Myriam
name: Rice, Kenneth M.
name: Rizzi, Federica
name: Rosenkranz, Alexander R.
name: Rossing, Peter
name: Rotter, Jerome I.
name: Ruggiero, Daniela
name: Ryan, Kathleen A.
name: Sabanayagam, Charumathi
name: Salvi, Erika
name: Schmidt, Helena
name: Schmidt, Reinhold
name: Scholz, Markus
name: Schöttker, Ben
name: Schulz, Christina-Alexandra
name: Sedaghat, Sanaz
name: Shaffer, Christian M.
name: Sieber, Karsten B.
name: Sim, Xueling
name: Sims, Mario
name: Snieder, Harold
name: Stanzick, Kira J.
name: Thorsteinsdottir, Unnur
name: Stocker, Hannah
name: Strauch, Konstantin
name: Stringham, Heather M.
name: Sulem, Patrick
name: Szymczak, Silke
name: Taylor, Kent D.
name: Thio, Chris H. L.
name: Tremblay, Johanne
name: Vaccargiu, Simona
name: van der Harst, Pim
name: van der Most, Peter J.
name: Verweij, Niek
name: Völker, Uwe
name: Wakai, Kenji
name: Waldenberger, Melanie
name: Wallentin, Lars
name: Wallner, Stefan
name: Wang, Judy
name: Waterworth, Dawn M.
name: White, Harvey D.
name: Willer, Cristen J.
name: Wong, Tien-Yin
name: Woodward, Mark
name: Yang, Qiong
name: Yerges-Armstrong, Laura M.
name: Zimmermann, Martina E.
name: Zonderman, Alan B.
name: Bergler, Tobias
name: Stefansson, Kari
name: Böger, Carsten A.
name: Pattaro, Cristian
name: Köttgen, Anna
name: Kronenberg, Florian
name: Heid, Iris M.
Publisher: name: Universität Regensburg
Year: 2022
Subjects: subject: CLINICAL-PRACTICE; BASE-LINE; DISEASE; PROGRESSION; SHROOM3; ADJUSTMENT; VARIANTS; EXAMPLE; RISK; BIAS; acute kidney injury; chronic kidney disease; diabetes; gene expression
subject: 610 Medizin

description: 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.