Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies

Gorski M, Rasheed H, Teumer A, Thomas LF, Graham SE, Sveinbjornsson G, Winkler TW, Günther F, Stark KJ, Chai JF, Tayo BO, Wuttke M, Li Y, Tin A, Ahluwalia TS, Ärnlöv J, Åsvold BO, Bakker SJ, Banas B, Bansal N, Biggs ML, Biino G, Böhnke M, Boerwinkle E, Bottinger EP, Brenner H, Brumpton B, Carroll RJ, Chaker L, Chalmers J, Chee ML, Chee ML, Cheng CY, Chu AY, Ciullo M, Cocca M, Cook JP, Coresh J, Cusi D, de Borst MH, Degenhardt F, Eckardt KU, Endlich K, Evans MK, Feitosa MF, Franke A, Freitag-Wolf S, Fuchsberger C, Gampawar P, Gansevoort RT, Ghanbari M, Ghasemi S, Giedraitis V, Gieger C, Gudbjartsson DF, Hallan S, Hamet P, Hishida A, Ho K, Hofer E, Holleczek B, Holm H, Hoppmann A, Horn K, Hutri-Kähönen N, Hveem K, Hwang SJ, Ikram MA, Josyula NS, Jung B, Kähönen M, Karabegović I, Khor CC, Koenig W, Kramer H, Krämer BK, Kühnel B, Kuusisto J, Laakso M, Lange LA, Lehtimäki T, Li M, Lieb W, Lind L, Lindgren CM, Loos RJ, Lukas MA, Lyytikäinen LP, Mahajan A, Matias-Garcia PR, Meisinger C, Meitinger T, Melander O, Milaneschi Y, Mishra PP, Mononen N, Morris AP, Mychaleckyj JC, Nadkarni GN, Naito M, Nakatochi M, Nalls MA, Nauck M, Nikus K, Ning B, Nolte IM, Nutile T, O'Donoghue ML, O'Connell J, Olafsson I, Orho-Melander M, Parsa A, Pendergrass SA, Penninx BW, Pirastu M, Preuss MH, Psaty BM, Raffield LM, Raitakari OT, Rheinberger M, Rice KM, Rizzi F, Rosenkranz AR, Rossing P, Rotter JI, Ruggiero D, Ryan KA, Sabanayagam C, Salvi E, Schmidt H, Schmidt R, Scholz M, Schöttker B, Schulz CA, Sedaghat S, Shaffer CM, Sieber KB, Sim X, Sims M, Snieder H, Stanzick KJ, Thorsteinsdottir U, Stocker H, Strauch K, Stringham HM, Sulem P, Szymczak S, Taylor KD, Thio CH, Tremblay J, Vaccargiu S, van der Harst P, van der Most PJ, Verweij N, Völker U, Wakai K, Waldenberger M, Wallentin L, Wallner S, Wang J, Waterworth DM, White HD, Willer CJ, Wong TY, Woodward M, Yang Q, Yerges-Armstrong LM, Zimmermann M, Zonderman AB, Bergler T, Stefansson K, Böger CA, Pattaro C, Köttgen A, Kronenberg F, Heid IM (2022)

Publication Type: Journal article

Publication year: 2022

Journal

DOI: 10.1016/j.kint.2022.05.021

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.

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Involved external institutions

Christian-Albrechts-Universität zu Kiel Germany (DE) University of Washington United States (USA) (US) Johns Hopkins University (JHU) United States (USA) (US) Vanderbilt University United States (USA) (US) Washington University United States (USA) (US) University of Texas Health Science Center at Houston (UTHealth) United States (USA) (US) Icahn School of Medicine at Mount Sinai United States (USA) (US) The University of Liverpool United Kingdom (GB) NTNU Trondheim - Norwegian University of Science and Technology Norway (NO) University of Michigan–Ann Arbor United States (USA) (US) Universitätsklinikum Regensburg Germany (DE) I.R.C.C.S. materno infantile Burlo Garofolo Italy (IT) deCODE genetics Iceland (IS) Consiglio Nazionale delle Ricerche (CNR) / National Research Council of Italy Italy (IT) Universitätsmedizin Greifswald / Universitätsklinikum Greifswald Germany (DE) Universität Regensburg Germany (DE) National University of Singapore (NUS) Singapore (SG) Universitätsklinikum Freiburg Germany (DE) National Institute on Aging (NIA) United States (USA) (US) University of Virginia (UVA) United States (USA) (US) Karolinska Institute Sweden (SE) University of Amsterdam Netherlands (NL) Medizinische Universität Graz Austria (AT) University of New South Wales (UNSW) Australia (AU) Fimlab Laboratories Finland (FI) Universität Leipzig Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Nagoya University / 名古屋大学 Japan (JP) Tampere University Hospital / Tampereen yliopistollinen sairaala (TAYS) Finland (FI) Erasmus University Medical Center (MC) Netherlands (NL) Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.) Germany (DE) University of Michigan United States (USA) (US) Institute of genetics and biophysics "Adriano Buzzati Traverso" (IGB) Italy (IT) Lund University / Lunds universitet Sweden (SE) Auckland City Hospital New Zealand (NZ) GlaxoSmithKline Research and Development United States (USA) (US) Steno Diabetes Center Denmark (DK) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich Germany (DE) Centre hospitalier de l'Université de Montréal (CHUM) Canada (CA) University of Mississippi Medical Center United States (USA) (US) Framingham Heart Study United States (USA) (US) University of Utah United States (USA) (US) Universitätsklinikum Mannheim Germany (DE) Kuopio University Hospital / Pohjois-Savon sairaanhoitopiiri Finland (FI) Università degli studi di Milano Italy (IT) University Medical Center Groningen (UMCG) / Universitair Medisch Centrum Groningen Netherlands (NL) Merck & Co., Inc. / Merck Sharp & Dohme Corp (MSD) United States (USA) (US) University of Maryland School of Pharmacy United States (USA) (US) Medizinische Universität Innsbruck Austria (AT) Geisinger Health System United States (USA) (US) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK / NIDDKD) United States (USA) (US) Brigham and Women's Hospital (BWH) United States (USA) (US) Landspítali / National University Hospital of Iceland Iceland (IS) University of North Carolina at Chapel Hill United States (USA) (US) Uppsala University Sweden (SE) Institute of Genetic and Biomedical Research / Istituto di Ricerca Genetica e Biomedica (IRGB CNR) Italy (IT) Harbor–UCLA Medical Center United States (USA) (US) Turku University Hospital / Turun yliopistollinen keskussairaala (TYKS) Finland (FI) Institute of Biomedical Technologies / Istituto di Tecnologie Biomediche (CNR ITB) Italy (IT) University of Oxford United Kingdom (GB) eurac research Italy (IT) Loyola University Chicago United States (USA) (US) University of Colorado Anschutz Medical Campus United States (USA) (US) Deutsches Herzzentrum München Germany (DE) Wellcome Centre for Human Genetics United Kingdom (GB)

How to cite

APA:

Gorski, M., Rasheed, H., Teumer, A., Thomas, L.F., Graham, S.E., Sveinbjornsson, G.,... Heid, I.M. (2022). Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies. Kidney International. https://doi.org/10.1016/j.kint.2022.05.021

MLA:

Gorski, Mathias, et al. "Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies." Kidney International (2022).

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