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

Funding Information: The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) supported the meta-analysis—Project-ID 387509280—SFB1350 (Subproject C6 to I.M.H.). A.M.H., B.R., and R.T. were supported by VACSR&D MVP grant CX001897. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by VACSR&D MVP grant CX001897 (A.M.H.). This publication does not represent the views of the Department of Veteran Affairs or the United States Government. We conducted this research using the UK Biobank resource under the application number 20272. We thank Paola Bilani for collecting author information. Extended acknowledgements are provided in Supplementary Note for all studies, in Supplementary Note for MVP and in Supplementary Note for LifeLines. Funding Information: GlaxoSmithKline and Merck & Co employed A.Y.C. Janssen Pharmaceuticals and GlaxoSmithKline employed D.M.W. K.B.S., L.M.Y.-A. and M.A.L. are full-time employees of GlaxoSmithKline. M.S. receives funding from Pfizer Inc. for a project not related to this research. J.Ä. reports personal fees from AstraZeneca, Boehringer Ingelheim and Novartis, outside of the submitted work. D.F.G., H.H., K.S., P.S., G.S. and U.T. are employees of deCODE/Amgen Inc. Kevin Ho received support by Fresenius Medical Care North America. M.K. is employed with Synlab Holding Deutschland GmbH. W.K. reports consulting fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daiichi-Sankyo, Genentech, Novo Nordisk, Esperion, OMEICOS, LIB Therapeutics, speaker honoraria from Amgen, AstraZeneca, Novartis, Berlin-Chemie, Sanofi, and Bristol-Myers Squibb, and grants and non-financial support from Abbott, Roche Diagnostics, Beckmann, and Singulex, outside the submitted work. C.L. received Grants/ Research Support from Bayer Ag/ Novo Nordisk, Husband works for Vertex. As of January 2020, A.M. is an employee of Genentech, and a holder of Roche stock. W.M. is employed with Synlab Holding Deutschland GmbH. D.O.M.-K. is a partime research physician at Metabolon, Inc. M.A.N. was supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA and consults for a number of small biotech and pharma. M.L.O. received grant support from GlaxoSmithKline during conduct of the study and received support from Novartis, Merck, Amgen, and AstraZeneca. L.S.P. has served on Scientific Advisory Boards for Janssen, and has or had research support from Merck, Pfizer, Eli Lilly, Novo Nordisk, Sanofi, PhaseBio, Roche, Abbvie, Vascular Pharmaceuticals, Janssen, Glaxo SmithKline, and the Cystic Fibrosis Foundation. He is also a cofounder, Officer and Board member and stockholder for a company, Diasyst, Inc., which markets software aimed to help improve diabetes management. A.I.P. and D.F.R. are employees of Merck Sharp Dohme Corp. Bruce.M.P. serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. P.R. received fees to his institution for research support from AstraZeneca and Novo Nordisk; for steering group participation from AstraZeneca, Gilead, Novo Nordisk, and Bayer; for lectures from Bayer, Eli Lilly and Novo Nordisk; and for advisory boards from Sanofi and Boehringer Ingelheim outside of this work. V.S. has received a modest honorarium from Sanofi for consulting. He also has ongoing research collaboration with Bayer Ltd. (all outside of the present study). L.W. received institutional grants from GlaxoSmithKline, AstraZeneca, BMS, Boehringer-Ingelheim, Pfizer, MSD and Roche Diagnostics. H.W. has received grant support paid to the institution and fees for serving on Steering Committees of the ODYSSEY trial from Sanofi and Regeneron Pharmaceuticals, the ISCHEMIA and the MINT studies from the National Institutes of Health, the STRENGTH trial from Omthera Pharmaceuticals, the HEART-FID study from American Regent, the DAL-GENE study from DalCor Pharma UK Inc., the AEGIS-II study from CSL Behring, the SCORED and SOLOIST-WHF from Sanofi Aventis Australia Pty. Ltd., and the CLEAR OUTCOMES study from Esperion Therapeutics. M.P. is partly funded by the study FinnGen ( www.finngen.fi ), which is jointly funded by a Finnish Governmental agency Business Finland and thirteen international pharmaceutical companies: Abbvie, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, a member of the Roche Group, GlaxoSmithKline (GSK), Janssen, Maze Therapeutics, MSD (the tradename of Merck & Co., Inc, Kenilworth, NJ USA), Novartis, Pfizer and Sanofi. C.C.K. is an Editorial Board Member for Communications Biology, but was not involved in the editorial review of, nor the decision to publish this article. The remaining authors declare no competing interests. Funding Information: The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) supported the meta-analysis—Project-ID 387509280—SFB1350 (Subproject C6 to I.M.H.). A.M.H., B.R., and R.T. were supported by VACSR&D MVP grant CX001897. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by VACSR&D MVP grant CX001897 (A.M.H.). This publication does not represent the views of the Department of Veteran Affairs or the United States Government. We conducted this research using the UK Biobank resource under the application number 20272. We thank Paola Bilani for collecting author information. Extended acknowledgements are provided in Supplementary Note 4 for all studies, in Supplementary Note 5 for MVP and in Supplementary Note 6 for LifeLines. Publisher Copyright: © 2022, The Author(s).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 (nDM = 178,691, nnoDM = 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.Peer reviewe