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

LifeLines Cohort Study; VA Million Veteran Program; 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 Li; Markus 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; Andres Metspalu; Andrew A Hicks; Andrew P. Morris; Anke Tönjes; Anna Morgan; Anna I. Podgornaia; Annette Peters; Antje Körner; Anubha Mahajan; Archie Campbell; Blair H. Smith; Iris M. Heid

doi:10.1038/s42003-022-03448-z

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

LifeLines Cohort Study, , VA Million Veteran Program, Thomas W. Winkler (Lead / Corresponding author), 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, Andres Metspalu, Andrew A Hicks, Andrew P. Morris, Anke Tönjes, Anna Morgan, Anna I. Podgornaia, Annette Peters, Antje Körner, Anubha Mahajan, Archie Campbell, Blair H. Smith, Iris M. Heid (Lead / Corresponding author)

Population Health and Genomics

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Abstract

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.

Original language	English
Article number	580
Number of pages	20
Journal	Communications Biology
Volume	5
DOIs	https://doi.org/10.1038/s42003-022-03448-z
Publication status	Published - 13 Jun 2022

Keywords

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

ASJC Scopus subject areas

General Agricultural and Biological Sciences
General Biochemistry,Genetics and Molecular Biology
Medicine (miscellaneous)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Final Published VersionFinal published version, 5.55 MBLicence: CC BY
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LifeLines Cohort Study, VA Million Veteran Program, Winkler, T. W., Rasheed, H., Teumer, A., Gorski, M., Rowan, B. X., Stanzick, K. J., Thomas, L. F., Tin, A., Hoppmann, A., Chu, A. Y., Tayo, B., Thio, C. H. L., Cusi, D., Chai, J.-F., Sieber, K. B., Horn, K., ... Heid, I. M. (2022). Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals. Communications Biology, 5, Article 580. https://doi.org/10.1038/s42003-022-03448-z

@article{24153976d4ca4ed3a42edae94beb1ea8,

title = "Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals",

abstract = "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.",

keywords = "Creatinine, Diabetes Mellitus, Diabetic Nephropathies/genetics, Genome-Wide Association Study, Glomerular Filtration Rate/genetics, Humans, Kidney",

author = "{LifeLines Cohort Study} and {VA Million Veteran Program} and Winkler, {Thomas W.} and Humaira Rasheed and Alexander Teumer and Mathias Gorski and Rowan, {Bryce X.} and Stanzick, {Kira J.} and Thomas, {Laurent F.} and Adrienne Tin and Anselm Hoppmann and Chu, {Audrey Y.} and Bamidele Tayo and Thio, {Chris H. L.} and Daniele Cusi and Jin-Fang Chai and Sieber, {Karsten B.} and Katrin Horn and Man Li and Markus Scholz and Massimiliano Cocca and Matthias Wuttke and {van der Most}, {Peter J.} and Qiong Yang and Sahar Ghasemi and Teresa Nutile and Yong Li and Giulia Pontali and Felix G{\"u}nther and Abbas Dehghan and Adolfo Correa and Afshin Parsa and Agnese Feresin and {de Vries}, {Aiko P. J.} and Zonderman, {Alan B} and Smith, {Albert V.} and Oldehinkel, {Albertine J.} and {De Grandi}, Alessandro and Rosenkranz, {Alexander R.} and Andre Franke and Andrej Teren and Andres Metspalu and Hicks, {Andrew A} and Morris, {Andrew P.} and Anke T{\"o}njes and Anna Morgan and Podgornaia, {Anna I.} and Annette Peters and Antje K{\"o}rner and Anubha Mahajan and Archie Campbell and Smith, {Blair H.} and Heid, {Iris M.}",

note = "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.) {\textcopyright} 2022. The Author(s).",

year = "2022",

month = jun,

day = "13",

doi = "10.1038/s42003-022-03448-z",

language = "English",

volume = "5",

journal = "Communications Biology",

issn = "2399-3642",

publisher = "Springer Nature",

}

LifeLines Cohort Study, VA Million Veteran Program, Winkler, TW, Rasheed, H, Teumer, A, Gorski, M, Rowan, BX, Stanzick, KJ, Thomas, LF, Tin, A, Hoppmann, A, Chu, AY, Tayo, B, Thio, CHL, Cusi, D, Chai, J-F, Sieber, KB, Horn, K, Li, M, Scholz, M, Cocca, M, Wuttke, M, van der Most, PJ, Yang, Q, Ghasemi, S, Nutile, T, Li, Y, Pontali, G, Günther, F, Dehghan, A, Correa, A, Parsa, A, Feresin, A, de Vries, APJ, Zonderman, AB, Smith, AV, Oldehinkel, AJ, De Grandi, A, Rosenkranz, AR, Franke, A, Teren, A, Metspalu, A, Hicks, AA, Morris, AP, Tönjes, A, Morgan, A, Podgornaia, AI, Peters, A, Körner, A, Mahajan, A, Campbell, A & Smith, BH & Heid, IM 2022, 'Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals', Communications Biology, vol. 5, 580. https://doi.org/10.1038/s42003-022-03448-z

TY - JOUR

T1 - Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

AU - LifeLines Cohort Study

AU - VA Million Veteran Program

AU - Winkler, Thomas W.

AU - Rasheed, Humaira

AU - Teumer, Alexander

AU - Gorski, Mathias

AU - Rowan, Bryce X.

AU - Stanzick, Kira J.

AU - Thomas, Laurent F.

AU - Tin, Adrienne

AU - Hoppmann, Anselm

AU - Chu, Audrey Y.

AU - Tayo, Bamidele

AU - Thio, Chris H. L.

AU - Cusi, Daniele

AU - Chai, Jin-Fang

AU - Sieber, Karsten B.

AU - Horn, Katrin

AU - Li, Man

AU - Scholz, Markus

AU - Cocca, Massimiliano

AU - Wuttke, Matthias

AU - van der Most, Peter J.

AU - Yang, Qiong

AU - Ghasemi, Sahar

AU - Nutile, Teresa

AU - Li, Yong

AU - Pontali, Giulia

AU - Günther, Felix

AU - Dehghan, Abbas

AU - Correa, Adolfo

AU - Parsa, Afshin

AU - Feresin, Agnese

AU - de Vries, Aiko P. J.

AU - Zonderman, Alan B

AU - Smith, Albert V.

AU - Oldehinkel, Albertine J.

AU - De Grandi, Alessandro

AU - Rosenkranz, Alexander R.

AU - Franke, Andre

AU - Teren, Andrej

AU - Metspalu, Andres

AU - Hicks, Andrew A

AU - Morris, Andrew P.

AU - Tönjes, Anke

AU - Morgan, Anna

AU - Podgornaia, Anna I.

AU - Peters, Annette

AU - Körner, Antje

AU - Mahajan, Anubha

AU - Campbell, Archie

AU - Smith, Blair H.

AU - Heid, Iris M.

N1 - 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.) © 2022. The Author(s).

PY - 2022/6/13

Y1 - 2022/6/13

N2 - 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.

AB - 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.

KW - Creatinine

KW - Diabetes Mellitus

KW - Diabetic Nephropathies/genetics

KW - Genome-Wide Association Study

KW - Glomerular Filtration Rate/genetics

KW - Humans

KW - Kidney

UR - http://www.scopus.com/inward/record.url?scp=85131867525&partnerID=8YFLogxK

U2 - 10.1038/s42003-022-03448-z

DO - 10.1038/s42003-022-03448-z

M3 - Article

C2 - 35697829

SN - 2399-3642

VL - 5

JO - Communications Biology

JF - Communications Biology

M1 - 580

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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