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

Lifelines Cohort Study, VA Million Veteran Program, DiscovEHR/MyCode , Thomas W Winkler*, Humaira Rasheed, Alexander Teumer, Mathias Gorski, Bryce X Rowan, Kira J Stanzick, Laurent F Thomas, Adrienne Tin, Anselm Hoppmann, Audrey Y Chu, Bamidele Tayo, Chris H L Thio, Daniele Cusi, Jin-Fang Chai, Karsten B Sieber, Katrin Horn, Man LiMarkus Scholz, Massimiliano Cocca, Matthias Wuttke, Peter J van der Most, Qiong Yang, Sahar Ghasemi, Teresa Nutile, Yong Li, Giulia Pontali, Felix Günther, Abbas Dehghan, Adolfo Correa, Afshin Parsa, Agnese Feresin, Aiko P J de Vries, Alan B Zonderman, Albert V Smith, Albertine J Oldehinkel, Alessandro De Grandi, Alexander R Rosenkranz, Andre Franke, Andrej Teren, Brenda W J H Penninx, Catharina A Hartman, Harold Snieder, Ilja M Nolte, Martin H de Borst, Niek Verweij, Pim van der Harst, Ron T Gansevoort, Stephan J L Bakker, Wei Huang, Ya Xing Wang, Iris M. Heid*

*Corresponding author for this work

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Abstract

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.

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.

Original languageEnglish
Article number580
Number of pages20
JournalCommunications biology
Volume5
Issue number1
DOIs
Publication statusPublished - 13-Jun-2022

Keywords

  • Creatinine
  • Diabetes Mellitus
  • Diabetic Nephropathies/genetics
  • Genome-Wide Association Study
  • Glomerular Filtration Rate/genetics
  • Humans
  • Kidney

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