A1 Refereed original research article in a scientific journal
Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies
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, Y.Chu Audrey, 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., M.Raffield Laura, 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.; Lifelines Cohort Study
Publisher: Elsevier
Publication year: 2022
Journal: Kidney International
Journal name in source: Kidney international
Journal acronym: Kidney Int
Volume: 102
Issue: 3
First page : 624
Last page: 639
ISSN: 0085-2538
eISSN: 1523-1755
DOI: https://doi.org/10.1016/j.kint.2022.05.021
Web address : https://doi.org/10.1016/j.kint.2022.05.021
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/176090649
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.
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