Journal Article

DKFZ-2022-01294

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png 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, L. F. ; Graham, S. E. ; Sveinbjornsson, G. ; Winkler, T. W. ; Günther, F. ; Stark, K. J. ; Chai, J.-F. ; Tayo, B. O. ; Wuttke, M. ; Li, Y. ; Tin, A. ; Ahluwalia, T. S. ; Ärnlöv, J. ; Åsvold, B. O. ; Bakker, S. J. L. ; Banas, B. ; Bansal, N. ; Biggs, M. L. ; Biino, G. ; Böhnke, M. ; Boerwinkle, E. ; Bottinger, E. P. ; Brenner, H.DKFZ* ; Brumpton, B. ; Carroll, R. J. ; Chaker, L. ; Chalmers, J. ; Chee, M.-L. ; Chee, M.-L. ; Cheng, C.-Y. ; Chu, A. Y. ; Ciullo, M. ; Cocca, M. ; Cook, J. P. ; Coresh, J. ; Cusi, D. ; de Borst, M. H. ; Degenhardt, F. ; Eckardt, K.-U. ; Endlich, K. ; Evans, M. K. ; Feitosa, M. F. ; Franke, A. ; Freitag-Wolf, S. ; Fuchsberger, C. ; Gampawar, P. ; Gansevoort, R. T. ; Ghanbari, M. ; Ghasemi, S. ; Giedraitis, V. ; Gieger, C. ; Gudbjartsson, D. F. ; Hallan, S. ; Hamet, P. ; Hishida, A. ; Ho, K. ; Hofer, E. ; Holleczek, B.DKFZ* ; Holm, H. ; Hoppmann, A. ; Horn, K. ; Hutri-Kähönen, N. ; Hveem, K. ; Hwang, S.-J. ; Ikram, M. A. ; Josyula, N. S. ; Jung, B. ; Kähönen, M. ; Karabegović, I. ; Khor, C.-C. ; Koenig, W. ; Kramer, H. ; Krämer, B. K. ; Kühnel, B. ; Kuusisto, J. ; Laakso, M. ; Lange, L. A. ; Lehtimäki, T. ; Li, M. ; Lieb, W. ; study, L. c. (Collaboration Author) ; Lind, L. ; Lindgren, C. M. ; Loos, R. J. F. ; Lukas, M. A. ; Lyytikäinen, L.-P. ; Mahajan, A. ; Matias-Garcia, P. R. ; Meisinger, C. ; Meitinger, T. ; Melander, O. ; Milaneschi, Y. ; Mishra, P. P. ; Mononen, N. ; Morris, A. P. ; Mychaleckyj, J. C. ; Nadkarni, G. N. ; Naito, M. ; Nakatochi, M. ; Nalls, M. A. ; Nauck, M. ; Nikus, K. ; Ning, B. ; Nolte, I. M. ; Nutile, T. ; O'Donoghue, M. L. ; O'Connell, J. ; Olafsson, I. ; Orho-Melander, M. ; Parsa, A. ; Pendergrass, S. A. ; Penninx, B. W. J. H. ; Pirastu, M. ; Preuss, M. H. ; Psaty, B. M. ; Raffield, L. M. ; Raitakari, O. T. ; Rheinberger, M. ; Rice, K. M. ; Rizzi, F. ; Rosenkranz, A. R. ; Rossing, P. ; Rotter, J. I. ; Ruggiero, D. ; Ryan, K. A. ; Sabanayagam, C. ; Salvi, E. ; Schmidt, H. ; Schmidt, R. ; Scholz, M. ; Schöttker, B.DKFZ* ; Schulz, C.-A. ; Sedaghat, S. ; Shaffer, C. M. ; Sieber, K. B. ; Sim, X. ; Sims, M. ; Snieder, H. ; Stanzick, K. J. ; Thorsteinsdottir, U. ; Stocker, H.DKFZ* ; Strauch, K. ; Stringham, H. M. ; Sulem, P. ; Szymczak, S. ; Taylor, K. D. ; Thio, C. H. L. ; Tremblay, J. ; Vaccargiu, S. ; van der Harst, P. ; van der Most, P. J. ; Verweij, N. ; Völker, U. ; Wakai, K. ; Waldenberger, M. ; Wallentin, L. ; Wallner, S. ; Wang, J. ; Waterworth, D. M. ; White, H. D. ; Willer, C. J. ; Wong, T.-Y. ; Woodward, M. ; Yang, Q. ; Yerges-Armstrong, L. M. ; Zimmermann, M. ; Zonderman, A. B. ; Bergler, T. ; Stefansson, K. ; Böger, C. A. ; Pattaro, C. ; Köttgen, A. ; Kronenberg, F. ; Heid, I. M.

2022
Elsevier New York, NY

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Please use a persistent id in citations: 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.

Keyword(s): acute kidney injury ; chronic kidney disease ; diabetes ; gene expression

Note: 2022 Sep;102(3):624-639

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Contributing Institute(s):

1. C070 Klinische Epidemiologie und Alternf. (C070)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2022

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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