Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

• Published in: Communications biology 2022-06, Vol.5 (1), p.580-20, Article 580
• Main Authors: Winkler, Thomas W., Gorski, Mathias, Stanzick, Kira J., Thomas, Laurent F., Hoppmann, Anselm, Cusi, Daniele, Li, Man, Li, Yong, Correa, Adolfo, Feresin, Agnese, de Vries, Aiko P. J., Rosenkranz, Alexander R., Franke, Andre, Metspalu, Andres, Podgornaia, Anna I., Brumpton, Ben, Smith, Blair H., Ning, Boting, Hayward, Caroline, Hartman, Catharina A., Wang, Chaolong, Sabanayagam, Charumathi, Schulz, Christina-Alexandra, Porteous, David J., Waterworth, Dawn M., Mascalzoni, Deborah, Mook-Kanamori, Dennis O., Hofer, Edith, Salvi, Erika, Guilianini, Franco, Ehret, Georg, Waeber, Gerard, Pistis, Giorgio, Nadkarni, Girish N., Delgado, Graciela E., Montgomery, Grant W., Snieder, Harold, Gao, He, Holm, Hilma, Kramer, Holly, Tzoulaki, Ioanna, Martins, Jade, Halbritter, Jan, Felix, Janine F., Divers, Jasmin, Xu, Jie, Ärnlöv, Johan, Jakobsdottir, Johanna, Gaziano, John M., Jonas, Jost B., Mychaleckyj, Josyf C., Endlich, Karlhans, Ho, Kevin, Strauch, Konstantin, Hveem, Kristian, Lind, Lars, Yerges-Armstrong, Laura M., Raffield, Laura M., Phillips, Lawrence S., Klaric, Lucija, Ising, Marcus, Kleber, Marcus E., Concas, Maria Pina, Orho-Melander, Marju, Perola, Markus, Biggs, Mary L., Boehnke, Michael, Kuokkanen, Mikko, Bochud, Murielle, Josyula, Navya Shilpa, Schupf, Nicole, Verweij, Niek, Mononen, Nina, Bansal, Nisha, Devuyst, Olivier, Gasparini, Paolo, Magnusson, Patrik K. E., Hamet, Pavel, Kovacs, Peter, Vollenweider, Peter, van der Harst, Pim, Dorajoo, Rajkumar, Sim, Ralene Z. H., Noordam, Raymond, Schmidt, Reinhold, de Mutsert, Renée, Padmanabhan, Sandosh, Kerr, Shona M., Vaccargiu, Simona, Patil, Snehal B., Bakker, Stephan J. L., Vogelezang, Suzanne, Ahluwalia, Tarunveer S., Rabelink, Ton J., Salomaa, Veikko, Jaddoe, Vincent W. V., Gao, Xin, Sim, Xueling, Yu, Zhi, Stark, Klaus J.
• Format: Article
• Language: English
• Subjects: 45/43; 631/208/205/2138; 692/4022/1585/104; Basic Medicine; Biology; Biomedical and Life Sciences; Creatinine; Diabetes; Diabetes Mellitus; Diabetic Nephropathies; Diabetic Nephropathies - genetics; diabetic nephropathy; Drug development; Epidermal growth factor receptors; genetics; Genome-Wide Association Study; Genomes; Glomerular Filtration Rate; Glomerular Filtration Rate - genetics; glomerulus filtration rate; human; Humans; Kidney; Kidney diseases; Life Sciences; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Renal failure; Risk factors; Therapeutic targets
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-022-03448-z

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n DM  = 178,691, n noDM  = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN ) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM. A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.