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

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Authors: 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, SJL; 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; 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; Karabegovic, 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, RJF; 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, BWJH; 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, CHL; 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
Article Title: Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies.
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.
Journal Title: Kidney international
ISSN: 0085-2538
Publisher: Unknown  
Date Published: 2022