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

LifeLines Cohort Study, , Matthias Wuttke, Yong Li, Man Li, Karsten B. Sieber, Mary F. Feitosa, Mathias Gorski, Adrienne Tin, Lihua Wang, Audrey Y. Chu, Anselm Hoppmann, Holger Kirsten, Ayush Giri, Jin-Fang Chai, Gardar Sveinbjornsson, Bamidele O. Tayo, Teresa Nutile, Christian Fuchsberger, Jonathan Marten & 34 others Massimiliano Cocca, Sahar Ghasemi, Yizhe Xu, Katrin Horn, Damia Noce, Peter J. van der Most, Sanaz Sedaghat, Zhi Yu, Masato Akiyama, Saima Afaq, Tarunveer S. Ahluwalia, Peter Almgren, Najaf Amin, Johan Ärnlöv, Stephan J. L. Bakker, Nisha Bansal, Daniela Baptista, Sven Bergmann, Mary L. Biggs, Ginevra Biino, Michael Boehnke, Eric Boerwinkle, Mathilde Boissel, Erwin P. Bottinger, Thibaud S. Boutin, Hermann Brenner, Marco Brumat, Ralph Burkhardt, Adam S. Butterworth, Eric Campana, Archie Campbell, Blair H. Smith, Anna Köttgen, Cristian Pattaro

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)957-972
Number of pages16
JournalNature Genetics
Volume51
Issue number6
Early online date31 May 2019
DOIs
Publication statusPublished - Jun 2019

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Genetic Loci
Kidney
Glomerular Filtration Rate
Chronic Renal Insufficiency
Translational Medical Research
Genome-Wide Association Study
Blood Urea Nitrogen
Genes
Meta-Analysis
Public Health
Phenotype
Gene Expression

Cite this

LifeLines Cohort Study, Wuttke, M., Li, Y., Li, M., Sieber, K. B., ... Pattaro, C. (2019). A catalog of genetic loci associated with kidney function from analyses of a million individuals. Nature Genetics, 51(6), 957-972. https://doi.org/10.1038/s41588-019-0407-x
LifeLines Cohort Study ; Wuttke, Matthias ; Li, Yong ; Li, Man ; Sieber, Karsten B. ; Feitosa, Mary F. ; Gorski, Mathias ; Tin, Adrienne ; Wang, Lihua ; Chu, Audrey Y. ; Hoppmann, Anselm ; Kirsten, Holger ; Giri, Ayush ; Chai, Jin-Fang ; Sveinbjornsson, Gardar ; Tayo, Bamidele O. ; Nutile, Teresa ; Fuchsberger, Christian ; Marten, Jonathan ; Cocca, Massimiliano ; Ghasemi, Sahar ; Xu, Yizhe ; Horn, Katrin ; Noce, Damia ; van der Most, Peter J. ; Sedaghat, Sanaz ; Yu, Zhi ; Akiyama, Masato ; Afaq, Saima ; Ahluwalia, Tarunveer S. ; Almgren, Peter ; Amin, Najaf ; Ärnlöv, Johan ; Bakker, Stephan J. L. ; Bansal, Nisha ; Baptista, Daniela ; Bergmann, Sven ; Biggs, Mary L. ; Biino, Ginevra ; Boehnke, Michael ; Boerwinkle, Eric ; Boissel, Mathilde ; Bottinger, Erwin P. ; Boutin, Thibaud S. ; Brenner, Hermann ; Brumat, Marco ; Burkhardt, Ralph ; Butterworth, Adam S. ; Campana, Eric ; Campbell, Archie ; Smith, Blair H. ; Köttgen, Anna ; Pattaro, Cristian. / A catalog of genetic loci associated with kidney function from analyses of a million individuals. In: Nature Genetics. 2019 ; Vol. 51, No. 6. pp. 957-972.
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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 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 Jin-Fang Chai 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 Smith, {Blair H.} and Anna K{\"o}ttgen and Cristian Pattaro",
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LifeLines Cohort Study, Wuttke, M, Li, Y, Li, M, Sieber, KB, Feitosa, MF, Gorski, M, Tin, A, Wang, L, Chu, AY, Hoppmann, A, Kirsten, H, Giri, A, Chai, J-F, Sveinbjornsson, G, Tayo, BO, Nutile, T, Fuchsberger, C, Marten, J, Cocca, M, Ghasemi, S, Xu, Y, Horn, K, Noce, D, van der Most, PJ, Sedaghat, S, Yu, Z, Akiyama, M, Afaq, S, Ahluwalia, TS, Almgren, P, Amin, N, Ärnlöv, J, Bakker, SJL, Bansal, N, Baptista, D, Bergmann, S, Biggs, ML, Biino, G, Boehnke, M, Boerwinkle, E, Boissel, M, Bottinger, EP, Boutin, TS, Brenner, H, Brumat, M, Burkhardt, R, Butterworth, AS, Campana, E, Campbell, A, Smith, BH & Köttgen, A & Pattaro, C 2019, 'A catalog of genetic loci associated with kidney function from analyses of a million individuals', Nature Genetics, vol. 51, no. 6, pp. 957-972. https://doi.org/10.1038/s41588-019-0407-x

A catalog of genetic loci associated with kidney function from analyses of a million individuals. / LifeLines Cohort Study; Wuttke, Matthias; Li, Yong; Li, Man; Sieber, Karsten B.; Feitosa, Mary F.; Gorski, Mathias; Tin, Adrienne; Wang, Lihua; Chu, Audrey Y.; Hoppmann, Anselm; Kirsten, Holger; Giri, Ayush; Chai, Jin-Fang; Sveinbjornsson, Gardar; Tayo, Bamidele O.; Nutile, Teresa; Fuchsberger, Christian; Marten, Jonathan; Cocca, Massimiliano; Ghasemi, Sahar; Xu, Yizhe; Horn, Katrin; Noce, Damia; van der Most, Peter J.; Sedaghat, Sanaz; Yu, Zhi; Akiyama, Masato; Afaq, Saima; Ahluwalia, Tarunveer S.; Almgren, Peter; Amin, Najaf; Ärnlöv, Johan; Bakker, Stephan J. L.; Bansal, Nisha; Baptista, Daniela; Bergmann, Sven; Biggs, Mary L.; Biino, Ginevra; Boehnke, Michael; Boerwinkle, Eric; Boissel, Mathilde; Bottinger, Erwin P.; Boutin, Thibaud S.; Brenner, Hermann; Brumat, Marco; Burkhardt, Ralph; Butterworth, Adam S.; Campana, Eric; Campbell, Archie; Smith, Blair H.; Köttgen, Anna (Lead / Corresponding author); Pattaro, Cristian (Lead / Corresponding author).

In: Nature Genetics, Vol. 51, No. 6, 06.2019, p. 957-972.

Research output: Contribution to journalArticle

TY - JOUR

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

AU - LifeLines Cohort Study

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 - Smith, Blair H.

AU - Köttgen, Anna

AU - Pattaro, Cristian

PY - 2019/6

Y1 - 2019/6

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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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