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

Lifelines Cohort Study, V. A. Million Veteran Program

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftNature Genetics
Vol/bind51
Udgave nummer6
Sider (fra-til)957-972
ISSN1061-4036
DOI
StatusUdgivet - 1 jun. 2019

Fingeraftryk

Kidney
Glomerular Filtration Rate
Translational Medical Research
Genome-Wide Association Study
Meta-Analysis
Public Health

Citer dette

Lifelines Cohort Study ; V. A. Million Veteran Program. / A catalog of genetic loci associated with kidney function from analyses of a million individuals. I: Nature Genetics. 2019 ; Bind 51, Nr. 6. s. 957-972.
@article{302b686c1898440cb3caa5e0ed345518,
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 = "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 Kaare Christensen and {Lifelines Cohort Study} and {V. A. Million Veteran Program}",
year = "2019",
month = "6",
day = "1",
doi = "10.1038/s41588-019-0407-x",
language = "English",
volume = "51",
pages = "957--972",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "6",

}

A catalog of genetic loci associated with kidney function from analyses of a million individuals. / Lifelines Cohort Study; V. A. Million Veteran Program.

I: Nature Genetics, Bind 51, Nr. 6, 01.06.2019, s. 957-972.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

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

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 - Christensen, Kaare

AU - Lifelines Cohort Study

AU - V. A. Million Veteran Program

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.

U2 - 10.1038/s41588-019-0407-x

DO - 10.1038/s41588-019-0407-x

M3 - Journal article

VL - 51

SP - 957

EP - 972

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 6

ER -