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 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; 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

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, 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 voor dit werk

Onderzoeksoutput: Article › Academic › peer review

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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.

Originele taal-2	English
Artikelnummer	580
Aantal pagina's	20
Tijdschrift	Communications biology
Volume	5
Nummer van het tijdschrift	1
DOI's	https://doi.org/10.1038/s42003-022-03448-z
Status	Published - 13-jun.-2022

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10.1038/s42003-022-03448-zLicentie: CC BY

Differential and shared genetic effects on kidney function between diabetic and non-diabetic individualsFinal publisher's version, 5,53 MBLicentie: CC BY

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Lifelines Cohort Study, VA Million Veteran Program, DiscovEHR/MyCode , 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(1), Artikel 580. https://doi.org/10.1038/s42003-022-03448-z

@article{ef4416fb684e4bc39e600c9abe80b88f,

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

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.",

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 DiscovEHR/MyCode 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 Penninx, {Brenda W J H} and Hartman, {Catharina A} and Harold Snieder and Nolte, {Ilja M} and {de Borst}, {Martin H} and Niek Verweij and {van der Harst}, Pim and Gansevoort, {Ron T} and Bakker, {Stephan J L} and Wei Huang and Wang, {Ya Xing} and Heid, {Iris M.}",

note = "{\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 = "Nature Publishing Group",

number = "1",

}

Lifelines Cohort Study, VA Million Veteran Program, DiscovEHR/MyCode , 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, Penninx, BWJH, Hartman, CA , Snieder, H , Nolte, IM , de Borst, MH, Verweij, N, van der Harst, P , Gansevoort, RT , Bakker, SJL, Huang, W, Wang, YX & Heid, IM 2022, 'Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals', Communications biology, vol. 5, nr. 1, 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 - DiscovEHR/MyCode

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 - Penninx, Brenda W J H

AU - Hartman, Catharina A

AU - Snieder, Harold

AU - Nolte, Ilja M

AU - de Borst, Martin H

AU - Verweij, Niek

AU - van der Harst, Pim

AU - Gansevoort, Ron T

AU - Bakker, Stephan J L

AU - Huang, Wei

AU - Wang, Ya Xing

AU - Heid, Iris M.

PY - 2022/6/13

Y1 - 2022/6/13

N2 - 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.

AB - 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.

KW - Creatinine

KW - Diabetes Mellitus

KW - Diabetic Nephropathies/genetics

KW - Genome-Wide Association Study

KW - Glomerular Filtration Rate/genetics

KW - Humans

KW - Kidney

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

IS - 1

M1 - 580

ER -

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

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