A catalog of genetic loci associated with kidney function from analyses of a million individuals

Lifelines Cohort Study; V. A. Million Veteran Program

doi:10.1038/s41588-019-0407-x

A catalog of genetic loci associated with kidney function from analyses of a million individuals

Lifelines Cohort Study, V. A. Million Veteran Program

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

487 Scopus citations

Abstract

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

Original language	English (US)
Pages (from-to)	957-972
Number of pages	16
Journal	Nature Genetics
Volume	51
Issue number	6
DOIs	https://doi.org/10.1038/s41588-019-0407-x
State	Published - Jun 1 2019

Funding

is supported by a consulting contract between Data Tecnica International and the National Institute on Aging (NIA), National Institutes of Health (NIH) and consults for Illumina, the Michael J. Fox Foundation and University of California Healthcare. O.H.F. works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec); Metagenics; and AXA. K.B.S., L.Y.-A., D.M.W. and M.A.L. are full-time employees of GlaxoSmithKline. M.L.O’D. received grant support from GlaxoSmithKline, MSD, Eisai, AstraZeneca, MedCo and Janssen. H.W. received grants and non-financial support from GlaxoSmithKline, during the conduct of the study; grants from Sanofi-Aventis, Eli Lilly, the National Institute of Health, Omthera Pharmaceuticals, Pfizer New Zealand, Elsai Inc. and Dalcor Pharma UK; honoraria and non-financial support from AstraZeneca; and is on advisory boards for Sirtex and Acetilion and received personal fees from CSL Behring and American Regent outside the scope of the submitted work. L. Wallentin received institutional grants from GlaxoSmithKline, AstraZeneca, BMS, Boehringer-Ingelheim, Pfizer, MSD and Roche Diagnostics. D.F.R. and A.I.P. are employees of MSD. M. Scholz received consultancy of and grant support from Merck Serono not related to this project. B.M.P. serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. J. Danesh is a member of the Novartis Cardiovascular and Metabolic Advisory Board and received grant support from Novartis. A.S.B. received grants from MSD, Pfizer, Novartis, Biogen and Bioverativ and personal fees from Novartis. V.S. has participated in a conference trip sponsored by Novo Nordisk and received a honorarium from the same source for participating in an advisory board meeting. A. Köttgen received grant support from Gruenenthal. All other authors declare no conflicts of interest.

ASJC Scopus subject areas

Genetics

UN SDGs

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

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10.1038/s41588-019-0407-x

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@article{5977ef9491024becb97b0e833c90dfd5,

title = "A catalog of genetic loci associated with kidney function from analyses of a million individuals",

abstract = "Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.",

author = "{Lifelines Cohort Study} and {V. A. Million Veteran Program} and Matthias Wuttke and Yong Li and Man Li and Sieber, {Karsten B.} and Feitosa, {Mary F.} and Mathias Gorski and Adrienne Tin and Lihua Wang and Chu, {Audrey Y.} and Anselm Hoppmann and Holger Kirsten and Ayush Giri and Chai, {Jin Fang} and Gardar Sveinbjornsson and Tayo, {Bamidele O.} and Teresa Nutile and Christian Fuchsberger and Jonathan Marten and Massimiliano Cocca and Sahar Ghasemi and Yizhe Xu and Katrin Horn and Damia Noce and {van der Most}, {Peter J.} and Sanaz Sedaghat and Zhi Yu and Masato Akiyama and Saima Afaq and Ahluwalia, {Tarunveer S.} and Peter Almgren and Najaf Amin and Johan {\"A}rnl{\"o}v and Bakker, {Stephan J.L.} and Nisha Bansal and Daniela Baptista and Sven Bergmann and Biggs, {Mary L.} and Ginevra Biino and Michael Boehnke and Eric Boerwinkle and Mathilde Boissel and Bottinger, {Erwin P.} and Boutin, {Thibaud S.} and Hermann Brenner and Marco Brumat and Ralph Burkhardt and Butterworth, {Adam S.} and Eric Campana and Archie Campbell and Harry Campbell",

note = "Funding Information: is supported by a consulting contract between Data Tecnica International and the National Institute on Aging (NIA), National Institutes of Health (NIH) and consults for Illumina, the Michael J. Fox Foundation and University of California Healthcare. O.H.F. works in ErasmusAGE, a center for aging research across the life course funded by Nestl{\'e} Nutrition (Nestec); Metagenics; and AXA. K.B.S., L.Y.-A., D.M.W. and M.A.L. are full-time employees of GlaxoSmithKline. M.L.O{\textquoteright}D. received grant support from GlaxoSmithKline, MSD, Eisai, AstraZeneca, MedCo and Janssen. H.W. received grants and non-financial support from GlaxoSmithKline, during the conduct of the study; grants from Sanofi-Aventis, Eli Lilly, the National Institute of Health, Omthera Pharmaceuticals, Pfizer New Zealand, Elsai Inc. and Dalcor Pharma UK; honoraria and non-financial support from AstraZeneca; and is on advisory boards for Sirtex and Acetilion and received personal fees from CSL Behring and American Regent outside the scope of the submitted work. L. Wallentin received institutional grants from GlaxoSmithKline, AstraZeneca, BMS, Boehringer-Ingelheim, Pfizer, MSD and Roche Diagnostics. D.F.R. and A.I.P. are employees of MSD. M. Scholz received consultancy of and grant support from Merck Serono not related to this project. B.M.P. serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. J. Danesh is a member of the Novartis Cardiovascular and Metabolic Advisory Board and received grant support from Novartis. A.S.B. received grants from MSD, Pfizer, Novartis, Biogen and Bioverativ and personal fees from Novartis. V.S. has participated in a conference trip sponsored by Novo Nordisk and received a honorarium from the same source for participating in an advisory board meeting. A. K{\"o}ttgen received grant support from Gruenenthal. All other authors declare no conflicts of interest. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2019",

month = jun,

day = "1",

doi = "10.1038/s41588-019-0407-x",

language = "English (US)",

volume = "51",

pages = "957--972",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "6",

}

TY - JOUR

T1 - A catalog of genetic loci associated with kidney function from analyses of a million individuals

AU - Lifelines Cohort Study

AU - V. A. Million Veteran Program

AU - Wuttke, Matthias

AU - Li, Yong

AU - Li, Man

AU - Sieber, Karsten B.

AU - Feitosa, Mary F.

AU - Gorski, Mathias

AU - Tin, Adrienne

AU - Wang, Lihua

AU - Chu, Audrey Y.

AU - Hoppmann, Anselm

AU - Kirsten, Holger

AU - Giri, Ayush

AU - Chai, Jin Fang

AU - Sveinbjornsson, Gardar

AU - Tayo, Bamidele O.

AU - Nutile, Teresa

AU - Fuchsberger, Christian

AU - Marten, Jonathan

AU - Cocca, Massimiliano

AU - Ghasemi, Sahar

AU - Xu, Yizhe

AU - Horn, Katrin

AU - Noce, Damia

AU - van der Most, Peter J.

AU - Sedaghat, Sanaz

AU - Yu, Zhi

AU - Akiyama, Masato

AU - Afaq, Saima

AU - Ahluwalia, Tarunveer S.

AU - Almgren, Peter

AU - Amin, Najaf

AU - Ärnlöv, Johan

AU - Bakker, Stephan J.L.

AU - Bansal, Nisha

AU - Baptista, Daniela

AU - Bergmann, Sven

AU - Biggs, Mary L.

AU - Biino, Ginevra

AU - Boehnke, Michael

AU - Boerwinkle, Eric

AU - Boissel, Mathilde

AU - Bottinger, Erwin P.

AU - Boutin, Thibaud S.

AU - Brenner, Hermann

AU - Brumat, Marco

AU - Burkhardt, Ralph

AU - Butterworth, Adam S.

AU - Campana, Eric

AU - Campbell, Archie

AU - Campbell, Harry

N1 - Funding Information: is supported by a consulting contract between Data Tecnica International and the National Institute on Aging (NIA), National Institutes of Health (NIH) and consults for Illumina, the Michael J. Fox Foundation and University of California Healthcare. O.H.F. works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec); Metagenics; and AXA. K.B.S., L.Y.-A., D.M.W. and M.A.L. are full-time employees of GlaxoSmithKline. M.L.O’D. received grant support from GlaxoSmithKline, MSD, Eisai, AstraZeneca, MedCo and Janssen. H.W. received grants and non-financial support from GlaxoSmithKline, during the conduct of the study; grants from Sanofi-Aventis, Eli Lilly, the National Institute of Health, Omthera Pharmaceuticals, Pfizer New Zealand, Elsai Inc. and Dalcor Pharma UK; honoraria and non-financial support from AstraZeneca; and is on advisory boards for Sirtex and Acetilion and received personal fees from CSL Behring and American Regent outside the scope of the submitted work. L. Wallentin received institutional grants from GlaxoSmithKline, AstraZeneca, BMS, Boehringer-Ingelheim, Pfizer, MSD and Roche Diagnostics. D.F.R. and A.I.P. are employees of MSD. M. Scholz received consultancy of and grant support from Merck Serono not related to this project. B.M.P. serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. J. Danesh is a member of the Novartis Cardiovascular and Metabolic Advisory Board and received grant support from Novartis. A.S.B. received grants from MSD, Pfizer, Novartis, Biogen and Bioverativ and personal fees from Novartis. V.S. has participated in a conference trip sponsored by Novo Nordisk and received a honorarium from the same source for participating in an advisory board meeting. A. Köttgen received grant support from Gruenenthal. All other authors declare no conflicts of interest. Publisher Copyright: © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

AB - Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

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U2 - 10.1038/s41588-019-0407-x

DO - 10.1038/s41588-019-0407-x

M3 - Article

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AN - SCOPUS:85066607502

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VL - 51

SP - 957

EP - 972

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

A catalog of genetic loci associated with kidney function from analyses of a million individuals

Abstract

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UN SDGs

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