Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels

Adrienne Tin; Jonathan Marten; Victoria L. Halperin Kuhns; Yong Li; Matthias Wuttke; Holger Kirsten; Karsten B. Sieber; Chengxiang Qiu; Mathias Gorski; Zhi Yu; Ayush Giri; Gardar Sveinbjornsson; Man Li; Audrey Y. Chu; Anselm Hoppmann; Luke J. O'Connor; Bram Prins; Teresa Nutile; Damia Noce; Masato Akiyama; Massimiliano Cocca; Sahar Ghasemi; Peter J. van der Most; Katrin Horn; Yizhe Xu; Christian Fuchsberger; Sanaz Sedaghat; Saima Afaq; Najaf Amin; Johan Ärnlöv; Stephan J. L. Bakker; Nisha Bansal; Daniela Baptista; Sven Bergmann; Mary L. Biggs; Ginevra Biino; Eric Boerwinkle; Erwin P. Bottinger; Thibaud S. Boutin; Marco Brumat; Ralph Burkhardt; Eric Campana; Archie Campbell; Harry Campbell; Robert J. Carroll; Eulalia Catamo; John C. Chambers; Marina Ciullo; Maria Pina Concas; Blair H. Smith; Anna Köttgen

doi:10.1038/s41588-019-0504-x

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels

, Adrienne Tin (Lead / Corresponding author), Jonathan Marten, Victoria L. Halperin Kuhns, Yong Li, Matthias Wuttke, Holger Kirsten, Karsten B. Sieber, Chengxiang Qiu, Mathias Gorski, Zhi Yu, Ayush Giri, Gardar Sveinbjornsson, Man Li, Audrey Y. Chu, Anselm Hoppmann, Luke J. O'Connor, Bram Prins, Teresa Nutile, Damia NoceMasato Akiyama, Massimiliano Cocca, Sahar Ghasemi, Peter J. van der Most, Katrin Horn, Yizhe Xu, Christian Fuchsberger, Sanaz Sedaghat, Saima Afaq, Najaf Amin, Johan Ärnlöv, Stephan J. L. Bakker, Nisha Bansal, Daniela Baptista, Sven Bergmann, Mary L. Biggs, Ginevra Biino, Eric Boerwinkle, Erwin P. Bottinger, Thibaud S. Boutin, Marco Brumat, Ralph Burkhardt, Eric Campana, Archie Campbell, Harry Campbell, Robert J. Carroll, Eulalia Catamo, John C. Chambers, Marina Ciullo, Maria Pina Concas, Blair H. Smith, Anna Köttgen

Population Health and Genomics

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Abstract

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

Original language	English
Pages (from-to)	1459–1474
Number of pages	22
Journal	Nature Genetics
Volume	51
Issue number	10
Early online date	2 Oct 2019
DOIs	https://doi.org/10.1038/s41588-019-0504-x
Publication status	Published - Oct 2019

ASJC Scopus subject areas

Genetics

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Cite this

, Tin, A., Marten, J., Halperin Kuhns, V. L., Li, Y., Wuttke, M., Kirsten, H., Sieber, K. B., Qiu, C., Gorski, M., Yu, Z., Giri, A., Sveinbjornsson, G., Li, M., Chu, A. Y., Hoppmann, A., O'Connor, L. J., Prins, B., Nutile, T., ... Köttgen, A. (2019). Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels. Nature Genetics, 51(10), 1459–1474 . https://doi.org/10.1038/s41588-019-0504-x

@article{94caaa2b225749c2a839c37f81fc316b,

title = "Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels",

abstract = "Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.",

author = "Adrienne Tin and Jonathan Marten and {Halperin Kuhns}, {Victoria L.} and Yong Li and Matthias Wuttke and Holger Kirsten and Sieber, {Karsten B.} and Chengxiang Qiu and Mathias Gorski and Zhi Yu and Ayush Giri and Gardar Sveinbjornsson and Man Li and Chu, {Audrey Y.} and Anselm Hoppmann and O'Connor, {Luke J.} and Bram Prins and Teresa Nutile and Damia Noce and Masato Akiyama and Massimiliano Cocca and Sahar Ghasemi and {van der Most}, {Peter J.} and Katrin Horn and Yizhe Xu and Christian Fuchsberger and Sanaz Sedaghat and Saima Afaq 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 Eric Boerwinkle and Bottinger, {Erwin P.} and Boutin, {Thibaud S.} and Marco Brumat and Ralph Burkhardt and Eric Campana and Archie Campbell and Harry Campbell and Carroll, {Robert J.} and Eulalia Catamo and Chambers, {John C.} and Marina Ciullo and Concas, {Maria Pina} and Smith, {Blair H.} and Anna K{\"o}ttgen",

year = "2019",

month = oct,

doi = "10.1038/s41588-019-0504-x",

language = "English",

volume = "51",

pages = "1459–1474 ",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "10",

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Tin, A, Marten, J, Halperin Kuhns, VL, Li, Y, Wuttke, M, Kirsten, H, Sieber, KB, Qiu, C, Gorski, M, Yu, Z, Giri, A, Sveinbjornsson, G, Li, M, Chu, AY, Hoppmann, A, O'Connor, LJ, Prins, B, Nutile, T, Noce, D, Akiyama, M, Cocca, M, Ghasemi, S, van der Most, PJ, Horn, K, Xu, Y, Fuchsberger, C, Sedaghat, S, Afaq, S, Amin, N, Ärnlöv, J, Bakker, SJL, Bansal, N, Baptista, D, Bergmann, S, Biggs, ML, Biino, G, Boerwinkle, E, Bottinger, EP, Boutin, TS, Brumat, M, Burkhardt, R, Campana, E, Campbell, A, Campbell, H, Carroll, RJ, Catamo, E, Chambers, JC, Ciullo, M, Concas, MP & Smith, BH & Köttgen, A 2019, 'Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels', Nature Genetics, vol. 51, no. 10, pp. 1459–1474 . https://doi.org/10.1038/s41588-019-0504-x

TY - JOUR

T1 - Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels

AU - Tin, Adrienne

AU - Marten, Jonathan

AU - Halperin Kuhns, Victoria L.

AU - Li, Yong

AU - Wuttke, Matthias

AU - Kirsten, Holger

AU - Sieber, Karsten B.

AU - Qiu, Chengxiang

AU - Gorski, Mathias

AU - Yu, Zhi

AU - Giri, Ayush

AU - Sveinbjornsson, Gardar

AU - Li, Man

AU - Chu, Audrey Y.

AU - Hoppmann, Anselm

AU - O'Connor, Luke J.

AU - Prins, Bram

AU - Nutile, Teresa

AU - Noce, Damia

AU - Akiyama, Masato

AU - Cocca, Massimiliano

AU - Ghasemi, Sahar

AU - van der Most, Peter J.

AU - Horn, Katrin

AU - Xu, Yizhe

AU - Fuchsberger, Christian

AU - Sedaghat, Sanaz

AU - Afaq, Saima

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 - Boerwinkle, Eric

AU - Bottinger, Erwin P.

AU - Boutin, Thibaud S.

AU - Brumat, Marco

AU - Burkhardt, Ralph

AU - Campana, Eric

AU - Campbell, Archie

AU - Campbell, Harry

AU - Carroll, Robert J.

AU - Catamo, Eulalia

AU - Chambers, John C.

AU - Ciullo, Marina

AU - Concas, Maria Pina

AU - Smith, Blair H.

AU - Köttgen, Anna

PY - 2019/10

Y1 - 2019/10

N2 - Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

AB - Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

U2 - 10.1038/s41588-019-0504-x

DO - 10.1038/s41588-019-0504-x

M3 - Article

C2 - 31578528

SN - 1061-4036

VL - 51

SP - 1459

EP - 1474

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels

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