Meta-analyses identify DNA methylation associated with kidney function and damage

Pascal Schlosser; Adrienne Tin; The Estonian Biobank Research Team; Genetics of DNA Methylation Consortium (GoDMC); Pamela R. Matias-Garcia; Chris H.L. Thio; Roby Joehanes; Hongbo Liu; Antoine Weihs; Zhi Yu; Anselm Hoppmann; Franziska Grundner-Culemann; Josine L. Min; Adebowale A. Adeyemo; Charles Agyemang; Johan Ärnlöv; Nasir A. Aziz; Andrea Baccarelli; Murielle Bochud; Hermann Brenner; Monique M.B. Breteler; Cristian Carmeli; Layal Chaker; John C. Chambers; Shelley A. Cole; Josef Coresh; Tanguy Corre; Adolfo Correa; Simon R. Cox; Niek de Klein; Graciela E. Delgado; Arce Domingo-Relloso; Kai Uwe Eckardt; Arif B. Ekici; Karlhans Endlich; Kathryn L. Evans; James S. Floyd; Myriam Fornage; Lude Franke; Eliza Fraszczyk; Xu Gao; Xīn Gào; Mohsen Ghanbari; Sahar Ghasemi; Peter Henneman; Christian Herder; Yongmei Liu; Sanaz Sedaghat; Joyce B.J. van Meurs; Niek Verweij; Wei Zhao; Anna Köttgen; Alexander Teumer

doi:10.1038/s41467-021-27234-3

Meta-analyses identify DNA methylation associated with kidney function and damage

Pascal Schlosser^*, Adrienne Tin, The Estonian Biobank Research Team, Genetics of DNA Methylation Consortium (GoDMC), Pamela R. Matias-Garcia, Chris H.L. Thio, Roby Joehanes, Hongbo Liu, Antoine Weihs, Zhi Yu, Anselm Hoppmann, Franziska Grundner-Culemann, Josine L. Min, Adebowale A. Adeyemo, Charles Agyemang, Johan Ärnlöv, Nasir A. Aziz, Andrea Baccarelli, Murielle Bochud, Hermann BrennerMonique M.B. Breteler, Cristian Carmeli, Layal Chaker, John C. Chambers, Shelley A. Cole, Josef Coresh, Tanguy Corre, Adolfo Correa, Simon R. Cox, Niek de Klein, Graciela E. Delgado, Arce Domingo-Relloso, Kai Uwe Eckardt, Arif B. Ekici, Karlhans Endlich, Kathryn L. Evans, James S. Floyd, Myriam Fornage, Lude Franke, Eliza Fraszczyk, Xu Gao, Xīn Gào, Mohsen Ghanbari, Sahar Ghasemi, Peter Henneman, Christian Herder, Yongmei Liu, Sanaz Sedaghat, Joyce B.J. van Meurs, Niek Verweij, Wei Zhao, Anna Köttgen, Alexander Teumer

^*Corresponding author for this work

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Abstract

Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.

Original language	English
Article number	7174
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-27234-3
Publication status	Published - Dec 2021

Bibliographical note

Funding Information:
Johan Ärnlöv has served on advisory boards for AstraZeneca and Boehringer Ingelheim, and have received lecturing fees from AstraZeneca and Novartis, all unrelated to the present project. Josef Coresh received grants from NIH and consultant to healthy.io. James S. Floyd has consulted from Shionogi Inc. Christian Herder reports personal fees from Sanofi and Lilly and grant support from Sanofi outside the submitted work. Marcus Kleber is employed with SYNLAB Holding Deutschland GmbH. Wolfgang Koenig reports personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daichii-Sankyo, Genentech, Novo Nordisk, Omeicos, Esperion, Berlin-Chemie, Sanofi, and Bristol-Myers Squibb and grants and non-financial support from Abbott, Roche Diagnostics, Beckmann, and Singulex outside the submitted work. S. Lorkowski reports grants and personal fees from Akcea Therapeutics Germany, and personal fees from amedes, AMGEN, Berlin-Chemie, Boehringer Ingelheim Pharma, Daiichi Sankyo, Lilly Deutschland, MSD Sharp & Dohme, Novo Nordisk Pharma, Roche Pharma, Sanofi-Aventis, Synlab Holding Deutschland, Unilever and Upfield, all outside the submitted work. Riccardo E. Marioni has received payment from Illumina for presentations. Winfried März reports grants from Siemens Healthineers, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from AMGEN, grants from Astrazeneca, grants and personal fees from Sanofi, grants and personal fees from Alexion Pharmaceuticals, grants and personal fees from BASF, grants and personal fees from Abbott Diagnostics, grants and personal fees from Numares AG, grants and personal fees from Berlin-Chemie, grants and personal fees from Akzea Therapeutics, grants from Bayer Vital GmbH, grants from bestbion dx GmbH, grants from Boehringer Ingelheim Pharma GmbH Co KG, grants from Immundiagnostik GmbH, grants from Merck Chemicals GmbH, grants from MSD Sharp and Dohme GmbH, grants from Novartis Pharma GmbH, grants from Olink Proteomics, other from Synlab Holding Deutschland GmbH, all outside the submitted work. Bruce M. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Sylvia Rosas receives research funding through her institution for clinical trials from Bayer and Astra Zeneca. She has participated in advisory boards for Reata and Relypsa. Johan Sundström reports ownership in companies providing services to Itrim, Amgen, Janssen, Novo Nordisk, Eli Lilly, Boehringer, Bayer, Pfizer and AstraZeneca, outside the submitted work. Niek Verweij is currently employee of Regeneron Genetics Center. All other authors report no competing interests.

Publisher Copyright:
© 2021, The Author(s).

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Meta-analyses identify DNA methylation associated with kidney function and damageFinal published version, 3.77 MBLicence: CC BY

Cite this

Schlosser, P., Tin, A., The Estonian Biobank Research Team, Genetics of DNA Methylation Consortium (GoDMC), Matias-Garcia, P. R., Thio, C. H. L., Joehanes, R., Liu, H., Weihs, A., Yu, Z., Hoppmann, A., Grundner-Culemann, F., Min, J. L., Adeyemo, A. A., Agyemang, C., Ärnlöv, J., Aziz, N. A., Baccarelli, A., Bochud, M., ... Teumer, A. (2021). Meta-analyses identify DNA methylation associated with kidney function and damage. Nature Communications, 12(1), Article 7174. https://doi.org/10.1038/s41467-021-27234-3

@article{32aced2398304127b27c09e207ab479f,

title = "Meta-analyses identify DNA methylation associated with kidney function and damage",

abstract = "Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.",

author = "Pascal Schlosser and Adrienne Tin and {The Estonian Biobank Research Team} and {Genetics of DNA Methylation Consortium (GoDMC)} and Matias-Garcia, {Pamela R.} and Thio, {Chris H.L.} and Roby Joehanes and Hongbo Liu and Antoine Weihs and Zhi Yu and Anselm Hoppmann and Franziska Grundner-Culemann and Min, {Josine L.} and Adeyemo, {Adebowale A.} and Charles Agyemang and Johan {\"A}rnl{\"o}v and Aziz, {Nasir A.} and Andrea Baccarelli and Murielle Bochud and Hermann Brenner and Breteler, {Monique M.B.} and Cristian Carmeli and Layal Chaker and Chambers, {John C.} and Cole, {Shelley A.} and Josef Coresh and Tanguy Corre and Adolfo Correa and Cox, {Simon R.} and {de Klein}, Niek and Delgado, {Graciela E.} and Arce Domingo-Relloso and Eckardt, {Kai Uwe} and Ekici, {Arif B.} and Karlhans Endlich and Evans, {Kathryn L.} and Floyd, {James S.} and Myriam Fornage and Lude Franke and Eliza Fraszczyk and Xu Gao and Xīn G{\`a}o and Mohsen Ghanbari and Sahar Ghasemi and Peter Henneman and Christian Herder and Yongmei Liu and Sanaz Sedaghat and {van Meurs}, {Joyce B.J.} and Niek Verweij and Wei Zhao and Anna K{\"o}ttgen and Alexander Teumer",

note = "Funding Information: Johan {\"A}rnl{\"o}v has served on advisory boards for AstraZeneca and Boehringer Ingelheim, and have received lecturing fees from AstraZeneca and Novartis, all unrelated to the present project. Josef Coresh received grants from NIH and consultant to healthy.io. James S. Floyd has consulted from Shionogi Inc. Christian Herder reports personal fees from Sanofi and Lilly and grant support from Sanofi outside the submitted work. Marcus Kleber is employed with SYNLAB Holding Deutschland GmbH. Wolfgang Koenig reports personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daichii-Sankyo, Genentech, Novo Nordisk, Omeicos, Esperion, Berlin-Chemie, Sanofi, and Bristol-Myers Squibb and grants and non-financial support from Abbott, Roche Diagnostics, Beckmann, and Singulex outside the submitted work. S. Lorkowski reports grants and personal fees from Akcea Therapeutics Germany, and personal fees from amedes, AMGEN, Berlin-Chemie, Boehringer Ingelheim Pharma, Daiichi Sankyo, Lilly Deutschland, MSD Sharp & Dohme, Novo Nordisk Pharma, Roche Pharma, Sanofi-Aventis, Synlab Holding Deutschland, Unilever and Upfield, all outside the submitted work. Riccardo E. Marioni has received payment from Illumina for presentations. Winfried M{\"a}rz reports grants from Siemens Healthineers, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from AMGEN, grants from Astrazeneca, grants and personal fees from Sanofi, grants and personal fees from Alexion Pharmaceuticals, grants and personal fees from BASF, grants and personal fees from Abbott Diagnostics, grants and personal fees from Numares AG, grants and personal fees from Berlin-Chemie, grants and personal fees from Akzea Therapeutics, grants from Bayer Vital GmbH, grants from bestbion dx GmbH, grants from Boehringer Ingelheim Pharma GmbH Co KG, grants from Immundiagnostik GmbH, grants from Merck Chemicals GmbH, grants from MSD Sharp and Dohme GmbH, grants from Novartis Pharma GmbH, grants from Olink Proteomics, other from Synlab Holding Deutschland GmbH, all outside the submitted work. Bruce M. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Sylvia Rosas receives research funding through her institution for clinical trials from Bayer and Astra Zeneca. She has participated in advisory boards for Reata and Relypsa. Johan Sundstr{\"o}m reports ownership in companies providing services to Itrim, Amgen, Janssen, Novo Nordisk, Eli Lilly, Boehringer, Bayer, Pfizer and AstraZeneca, outside the submitted work. Niek Verweij is currently employee of Regeneron Genetics Center. All other authors report no competing interests. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41467-021-27234-3",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Schlosser, P, Tin, A, The Estonian Biobank Research Team, Genetics of DNA Methylation Consortium (GoDMC), Matias-Garcia, PR, Thio, CHL, Joehanes, R, Liu, H, Weihs, A, Yu, Z, Hoppmann, A, Grundner-Culemann, F, Min, JL, Adeyemo, AA, Agyemang, C, Ärnlöv, J, Aziz, NA, Baccarelli, A, Bochud, M, Brenner, H, Breteler, MMB, Carmeli, C, Chaker, L, Chambers, JC, Cole, SA, Coresh, J, Corre, T, Correa, A, Cox, SR, de Klein, N, Delgado, GE, Domingo-Relloso, A, Eckardt, KU, Ekici, AB, Endlich, K, Evans, KL, Floyd, JS, Fornage, M, Franke, L, Fraszczyk, E, Gao, X, Gào, X, Ghanbari, M, Ghasemi, S, Henneman, P, Herder, C, Liu, Y, Sedaghat, S, van Meurs, JBJ, Verweij, N, Zhao, W, Köttgen, A & Teumer, A 2021, 'Meta-analyses identify DNA methylation associated with kidney function and damage', Nature Communications, vol. 12, no. 1, 7174. https://doi.org/10.1038/s41467-021-27234-3

TY - JOUR

T1 - Meta-analyses identify DNA methylation associated with kidney function and damage

AU - Schlosser, Pascal

AU - Tin, Adrienne

AU - The Estonian Biobank Research Team

AU - Genetics of DNA Methylation Consortium (GoDMC)

AU - Matias-Garcia, Pamela R.

AU - Thio, Chris H.L.

AU - Joehanes, Roby

AU - Liu, Hongbo

AU - Weihs, Antoine

AU - Yu, Zhi

AU - Hoppmann, Anselm

AU - Grundner-Culemann, Franziska

AU - Min, Josine L.

AU - Adeyemo, Adebowale A.

AU - Agyemang, Charles

AU - Ärnlöv, Johan

AU - Aziz, Nasir A.

AU - Baccarelli, Andrea

AU - Bochud, Murielle

AU - Brenner, Hermann

AU - Breteler, Monique M.B.

AU - Carmeli, Cristian

AU - Chaker, Layal

AU - Chambers, John C.

AU - Cole, Shelley A.

AU - Coresh, Josef

AU - Corre, Tanguy

AU - Correa, Adolfo

AU - Cox, Simon R.

AU - de Klein, Niek

AU - Delgado, Graciela E.

AU - Domingo-Relloso, Arce

AU - Eckardt, Kai Uwe

AU - Ekici, Arif B.

AU - Endlich, Karlhans

AU - Evans, Kathryn L.

AU - Floyd, James S.

AU - Fornage, Myriam

AU - Franke, Lude

AU - Fraszczyk, Eliza

AU - Gao, Xu

AU - Gào, Xīn

AU - Ghanbari, Mohsen

AU - Ghasemi, Sahar

AU - Henneman, Peter

AU - Herder, Christian

AU - Liu, Yongmei

AU - Sedaghat, Sanaz

AU - van Meurs, Joyce B.J.

AU - Verweij, Niek

AU - Zhao, Wei

AU - Köttgen, Anna

AU - Teumer, Alexander

N1 - Funding Information: Johan Ärnlöv has served on advisory boards for AstraZeneca and Boehringer Ingelheim, and have received lecturing fees from AstraZeneca and Novartis, all unrelated to the present project. Josef Coresh received grants from NIH and consultant to healthy.io. James S. Floyd has consulted from Shionogi Inc. Christian Herder reports personal fees from Sanofi and Lilly and grant support from Sanofi outside the submitted work. Marcus Kleber is employed with SYNLAB Holding Deutschland GmbH. Wolfgang Koenig reports personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daichii-Sankyo, Genentech, Novo Nordisk, Omeicos, Esperion, Berlin-Chemie, Sanofi, and Bristol-Myers Squibb and grants and non-financial support from Abbott, Roche Diagnostics, Beckmann, and Singulex outside the submitted work. S. Lorkowski reports grants and personal fees from Akcea Therapeutics Germany, and personal fees from amedes, AMGEN, Berlin-Chemie, Boehringer Ingelheim Pharma, Daiichi Sankyo, Lilly Deutschland, MSD Sharp & Dohme, Novo Nordisk Pharma, Roche Pharma, Sanofi-Aventis, Synlab Holding Deutschland, Unilever and Upfield, all outside the submitted work. Riccardo E. Marioni has received payment from Illumina for presentations. Winfried März reports grants from Siemens Healthineers, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from AMGEN, grants from Astrazeneca, grants and personal fees from Sanofi, grants and personal fees from Alexion Pharmaceuticals, grants and personal fees from BASF, grants and personal fees from Abbott Diagnostics, grants and personal fees from Numares AG, grants and personal fees from Berlin-Chemie, grants and personal fees from Akzea Therapeutics, grants from Bayer Vital GmbH, grants from bestbion dx GmbH, grants from Boehringer Ingelheim Pharma GmbH Co KG, grants from Immundiagnostik GmbH, grants from Merck Chemicals GmbH, grants from MSD Sharp and Dohme GmbH, grants from Novartis Pharma GmbH, grants from Olink Proteomics, other from Synlab Holding Deutschland GmbH, all outside the submitted work. Bruce M. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Sylvia Rosas receives research funding through her institution for clinical trials from Bayer and Astra Zeneca. She has participated in advisory boards for Reata and Relypsa. Johan Sundström reports ownership in companies providing services to Itrim, Amgen, Janssen, Novo Nordisk, Eli Lilly, Boehringer, Bayer, Pfizer and AstraZeneca, outside the submitted work. Niek Verweij is currently employee of Regeneron Genetics Center. All other authors report no competing interests. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.

AB - Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.

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U2 - 10.1038/s41467-021-27234-3

DO - 10.1038/s41467-021-27234-3

M3 - Article

C2 - 34887417

AN - SCOPUS:85120946524

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 7174

ER -

Meta-analyses identify DNA methylation associated with kidney function and damage

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