Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies
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
https://urn.fi/URN:NBN:fi-fe2022091258784
Tiivistelmä
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.
Kokoelmat
- Rinnakkaistallenteet [27094]