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; Josef Coresh; Tanguy Corre; Daniele Cusi; Cinzia Felicita Sala; Martin H de Borst; Alessandro De Grandi; Renee de Mutsert; Aiko P. J. de Vries; Graciela Delgado; Ayşe Demirkan; Olivier Devuyst; Katalin Dittrich; Kai-Uwe Eckardt; Georg Ehret; Karlhans Endlich; Michele K. Evans; Ron T. Gansevoort; Paolo Gasparini; Vilmantas Giedraitis; Christian Gieger; Giorgia Girotto; Martin Gögele; Scott D. Gordon; Daniel F. Gudbjartsson; Vilmundur Gudnason; German Chronic Kidney Disease Study; Toomas Haller; Pavel Hamet; Tamara B. Harris; Caroline Hayward; Andrew A Hicks; Edith Hofer; Hilma Holm; Wei Huang; Nina Hutri-Kähönen; Shih-Jen Hwang; M. Arfan Ikram; Raychel M. Lewis; Erik Ingelsson; Johanna Jakobsdottir; Ingileif Jonsdottir; Helgi Jonsson; Peter K Joshi; Navya Shilpa Josyula; Bettina Jung; Mika Kähönen; Yoichiro Kamatani; Masahiro  Kanai; Shona M. Kerr; Wieland Kiess; Marcus E. Kleber; Wolfgang Koenig; Jaspal S. Kooner; Antje Körner; Peter Kovacs; Bernhard K. Krämer; Florian Kronenberg; Michiaki Kubo; Brigitte Kühnel; Martina La Bianca; Leslie A. Lange; Benjamin Lehne; Terho Lehtimäki; LifeLines Cohort Study; Jun Liu; Markus Loeffler; Ruth J. F. Loos; Leo-Pekka Lyytikäinen; Reedik Mägi; Anubha Mahajan; Nicholas G. Martin; Winfried März; Deborah Mascalzoni; Koichi Matsuda; Christa Meisinger; Thomas Meitinger; Andres Metspalu; Yuri Milaneschi; V. A. Million Veteran Program; Christopher J. O'Donnell; Otis D. Wilson; J. Michael Gaziano; Pashupati P. Mishra; Karen L. Mohlke; Nina Mononen; Grant W. Montgomery; Dennis O. Mook-Kanamori; Martina Müller-Nurasyid; Girish N. Nadkarni; Mike A. Nalls; Matthias Nauck; Kjell Nikus; Boting Ning; Ilja M. Nolte; Raymond Noordam; Jeffrey R. O'Connell; Isleifur Olafsson; Sandosh Padmanabhan; Brenda W. J. H. Penninx; Thomas Perls; Annette Peters; Mario Pirastu; Nicola Pirastu; Giorgio Pistis; Ozren Polasek; Belen Ponte; David J. Porteous; Tanja Poulain; Michael H. Preuss; Ton J. Rabelink; Laura M. Raffield; Olli T. Raitakari; Rainer Rettig; Myriam Rheinberger; Kenneth M. Rice; Federica Rizzi; Antonietta Robino; Igor Rudan; Alena Krajcoviechova; Renata Cifkova; Rico  Rueedi; Daniela Ruggiero; Kathleen A. Ryan; Yasaman Saba; Erika Salvi; Helena Schmidt; Reinhold Schmidt; Christian M. Shaffer; Albert V. Smith; Blair H. Smith; Cassandra N. Spracklen; Konstantin Strauch; Michael Stumvoll; Patrick Sulem; Salman M. Tajuddin; Andrej Teren; Joachim Thiery; Chris H. L. Thio; Unnur Thorsteinsdottir; Daniela Toniolo; Anke Tönjes; Johanne Tremblay; André G. Uitterlinden; Simona Vaccargiu; Pim van der Harst; Cornelia M. van Duijn; Niek Verweij; Uwe Völker; Peter Vollenweider; Gerard Waeber; Melanie Waldenberger; John B. Whitfield; Sarah H. Wild; James F. Wilson; Qiong Yang; Weihua Zhang; Alan B. Zonderman; Murielle Bochud; James G. Wilson; Sarah A. Pendergrass; Kevin Ho; Afshin Parsa; Peter P. Pramstaller; Bruce M. Psaty; Carsten A. Böger; Harold Snieder; Adam S. Butterworth; Yukinori Okada; Todd L. Edwards; Kari Stefansson; Katalin  Susztak; Markus Scholz; Iris M. Heid; Adriana M. Hung; Alexander Teumer; Cristian Pattaro; Owen M. Woodward; Veronique Vitart; Anna Köttgen

doi:10.1038/s41588-019-0504-x

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 AkiyamaMassimiliano 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, Josef Coresh, Tanguy Corre, Daniele Cusi, Cinzia Felicita Sala, Martin H de Borst, Alessandro De Grandi, Renee de Mutsert, Aiko P. J. de Vries, Graciela Delgado, Ayşe Demirkan, Olivier Devuyst, Katalin Dittrich, Kai-Uwe Eckardt, Georg Ehret, Karlhans Endlich, Michele K. Evans, Ron T. Gansevoort, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Martin Gögele, Scott D. Gordon, Daniel F. Gudbjartsson, Vilmundur Gudnason, German Chronic Kidney Disease Study, Toomas Haller, Pavel Hamet, Tamara B. Harris, Caroline Hayward, Andrew A Hicks, Edith Hofer, Hilma Holm, Wei Huang, Nina Hutri-Kähönen, Shih-Jen Hwang, M. Arfan Ikram, Raychel M. Lewis, Erik Ingelsson, Johanna Jakobsdottir, Ingileif Jonsdottir, Helgi Jonsson, Peter K Joshi, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Yoichiro Kamatani, Masahiro Kanai, Shona M. Kerr, Wieland Kiess, Marcus E. Kleber, Wolfgang Koenig, Jaspal S. Kooner, Antje Körner, Peter Kovacs, Bernhard K. Krämer, Florian Kronenberg, Michiaki Kubo, Brigitte Kühnel, Martina La Bianca, Leslie A. Lange, Benjamin Lehne, Terho Lehtimäki, LifeLines Cohort Study, Jun Liu, Markus Loeffler, Ruth J. F. Loos, Leo-Pekka Lyytikäinen, Reedik Mägi, Anubha Mahajan, Nicholas G. Martin, Winfried März, Deborah Mascalzoni, Koichi Matsuda, Christa Meisinger, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, V. A. Million Veteran Program, Christopher J. O'Donnell, Otis D. Wilson, J. Michael Gaziano, Pashupati P. Mishra, Karen L. Mohlke, Nina Mononen, Grant W. Montgomery, Dennis O. Mook-Kanamori, Martina Müller-Nurasyid, Girish N. Nadkarni, Mike A. Nalls, Matthias Nauck, Kjell Nikus, Boting Ning, Ilja M. Nolte, Raymond Noordam, Jeffrey R. O'Connell, Isleifur Olafsson, Sandosh Padmanabhan, Brenda W. J. H. Penninx, Thomas Perls, Annette Peters, Mario Pirastu, Nicola Pirastu, Giorgio Pistis, Ozren Polasek, Belen Ponte, David J. Porteous, Tanja Poulain, Michael H. Preuss, Ton J. Rabelink, Laura M. Raffield, Olli T. Raitakari, Rainer Rettig, Myriam Rheinberger, Kenneth M. Rice, Federica Rizzi, Antonietta Robino, Igor Rudan, Alena Krajcoviechova, Renata Cifkova, Rico Rueedi, Daniela Ruggiero, Kathleen A. Ryan, Yasaman Saba, Erika Salvi, Helena Schmidt, Reinhold Schmidt, Christian M. Shaffer, Albert V. Smith, Blair H. Smith, Cassandra N. Spracklen, Konstantin Strauch, Michael Stumvoll, Patrick Sulem, Salman M. Tajuddin, Andrej Teren, Joachim Thiery, Chris H. L. Thio, Unnur Thorsteinsdottir, Daniela Toniolo, Anke Tönjes, Johanne Tremblay, André G. Uitterlinden, Simona Vaccargiu, Pim van der Harst, Cornelia M. van Duijn, Niek Verweij, Uwe Völker, Peter Vollenweider, Gerard Waeber, Melanie Waldenberger, John B. Whitfield, Sarah H. Wild, James F. Wilson, Qiong Yang, Weihua Zhang, Alan B. Zonderman, Murielle Bochud, James G. Wilson, Sarah A. Pendergrass, Kevin Ho, Afshin Parsa, Peter P. Pramstaller, Bruce M. Psaty, Carsten A. Böger, Harold Snieder, Adam S. Butterworth, Yukinori Okada, Todd L. Edwards, Kari Stefansson, Katalin Susztak, Markus Scholz, Iris M. Heid, Adriana M. Hung, Alexander Teumer, Cristian Pattaro, Owen M. Woodward, Veronique Vitart, Anna Köttgen

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

Abstract / Description of output

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
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

Access to Document

10.1038/s41588-019-0504-x

AAM - Target genes variants tissues and transcriptional pathways...
This is the author’s peer-reviewed manuscript as accepted for publication.
Accepted author manuscript, 6.36 MB

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., Noce, D., ... 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{e66972d6605d4ee0b3810c83552d8dd1,

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{\textquoteright}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 Josef Coresh and Tanguy Corre and Daniele Cusi and Sala, {Cinzia Felicita} and {de Borst}, {Martin H} and {De Grandi}, Alessandro and {de Mutsert}, Renee and {de Vries}, {Aiko P. J.} and Graciela Delgado and Ay{\c s}e Demirkan and Olivier Devuyst and Katalin Dittrich and Kai-Uwe Eckardt and Georg Ehret and Karlhans Endlich and Evans, {Michele K.} and Gansevoort, {Ron T.} and Paolo Gasparini and Vilmantas Giedraitis and Christian Gieger and Giorgia Girotto and Martin G{\"o}gele and Gordon, {Scott D.} and Gudbjartsson, {Daniel F.} and Vilmundur Gudnason and {German Chronic Kidney Disease Study} and Toomas Haller and Pavel Hamet and Harris, {Tamara B.} and Caroline Hayward and Hicks, {Andrew A} and Edith Hofer and Hilma Holm and Wei Huang and Nina Hutri-K{\"a}h{\"o}nen and Shih-Jen Hwang and {Arfan Ikram}, M. and Lewis, {Raychel M.} and Erik Ingelsson and Johanna Jakobsdottir and Ingileif Jonsdottir and Helgi Jonsson and Joshi, {Peter K} and Josyula, {Navya Shilpa} and Bettina Jung and Mika K{\"a}h{\"o}nen and Yoichiro Kamatani and Masahiro Kanai and Kerr, {Shona M.} and Wieland Kiess and Kleber, {Marcus E.} and Wolfgang Koenig and Kooner, {Jaspal S.} and Antje K{\"o}rner and Peter Kovacs and Kr{\"a}mer, {Bernhard K.} and Florian Kronenberg and Michiaki Kubo and Brigitte K{\"u}hnel and {La Bianca}, Martina and Lange, {Leslie A.} and Benjamin Lehne and Terho Lehtim{\"a}ki and {LifeLines Cohort Study} and Jun Liu and Markus Loeffler and Loos, {Ruth J. F.} and Leo-Pekka Lyytik{\"a}inen and Reedik M{\"a}gi and Anubha Mahajan and Martin, {Nicholas G.} and Winfried M{\"a}rz and Deborah Mascalzoni and Koichi Matsuda and Christa Meisinger and Thomas Meitinger and Andres Metspalu and Yuri Milaneschi and {V. A. Million Veteran Program} and O'Donnell, {Christopher J.} and Wilson, {Otis D.} and Gaziano, {J. Michael} and Mishra, {Pashupati P.} and Mohlke, {Karen L.} and Nina Mononen and Montgomery, {Grant W.} and Mook-Kanamori, {Dennis O.} and Martina M{\"u}ller-Nurasyid and Nadkarni, {Girish N.} and Nalls, {Mike A.} and Matthias Nauck and Kjell Nikus and Boting Ning and Nolte, {Ilja M.} and Raymond Noordam and O'Connell, {Jeffrey R.} and Isleifur Olafsson and Sandosh Padmanabhan and Penninx, {Brenda W. J. H.} and Thomas Perls and Annette Peters and Mario Pirastu and Nicola Pirastu and Giorgio Pistis and Ozren Polasek and Belen Ponte and Porteous, {David J.} and Tanja Poulain and Preuss, {Michael H.} and Rabelink, {Ton J.} and Raffield, {Laura M.} and Raitakari, {Olli T.} and Rainer Rettig and Myriam Rheinberger and Rice, {Kenneth M.} and Federica Rizzi and Antonietta Robino and Igor Rudan and Alena Krajcoviechova and Renata Cifkova and Rico Rueedi and Daniela Ruggiero and Ryan, {Kathleen A.} and Yasaman Saba and Erika Salvi and Helena Schmidt and Reinhold Schmidt and Shaffer, {Christian M.} and Smith, {Albert V.} and Smith, {Blair H.} and Spracklen, {Cassandra N.} and Konstantin Strauch and Michael Stumvoll and Patrick Sulem and Tajuddin, {Salman M.} and Andrej Teren and Joachim Thiery and Thio, {Chris H. L.} and Unnur Thorsteinsdottir and Daniela Toniolo and Anke T{\"o}njes and Johanne Tremblay and Uitterlinden, {Andr{\'e} G.} and Simona Vaccargiu and {van der Harst}, Pim and {van Duijn}, {Cornelia M.} and Niek Verweij and Uwe V{\"o}lker and Peter Vollenweider and Gerard Waeber and Melanie Waldenberger and Whitfield, {John B.} and Wild, {Sarah H.} and Wilson, {James F.} and Qiong Yang and Weihua Zhang and Zonderman, {Alan B.} and Murielle Bochud and Wilson, {James G.} and Pendergrass, {Sarah A.} and Kevin Ho and Afshin Parsa and Pramstaller, {Peter P.} and Psaty, {Bruce M.} and B{\"o}ger, {Carsten A.} and Harold Snieder and Butterworth, {Adam S.} and Yukinori Okada and Edwards, {Todd L.} and Kari Stefansson and Katalin Susztak and Markus Scholz and Heid, {Iris M.} and Hung, {Adriana M.} and Alexander Teumer and Cristian Pattaro and Woodward, {Owen M.} and Veronique Vitart 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",

}

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, Coresh, J, Corre, T, Cusi, D, Sala, CF, de Borst, MH, De Grandi, A, de Mutsert, R, de Vries, APJ, Delgado, G, Demirkan, A, Devuyst, O, Dittrich, K, Eckardt, K-U, Ehret, G, Endlich, K, Evans, MK, Gansevoort, RT, Gasparini, P, Giedraitis, V, Gieger, C, Girotto, G, Gögele, M, Gordon, SD, Gudbjartsson, DF, Gudnason, V, German Chronic Kidney Disease Study, Haller, T, Hamet, P, Harris, TB, Hayward, C, Hicks, AA, Hofer, E, Holm, H, Huang, W, Hutri-Kähönen, N, Hwang, S-J, Arfan Ikram, M, Lewis, RM, Ingelsson, E, Jakobsdottir, J, Jonsdottir, I, Jonsson, H, Joshi, PK, Josyula, NS, Jung, B, Kähönen, M, Kamatani, Y, Kanai, M, Kerr, SM, Kiess, W, Kleber, ME, Koenig, W, Kooner, JS, Körner, A, Kovacs, P, Krämer, BK, Kronenberg, F, Kubo, M, Kühnel, B, La Bianca, M, Lange, LA, Lehne, B, Lehtimäki, T, LifeLines Cohort Study, Liu, J, Loeffler, M, Loos, RJF, Lyytikäinen, L-P, Mägi, R, Mahajan, A, Martin, NG, März, W, Mascalzoni, D, Matsuda, K, Meisinger, C, Meitinger, T, Metspalu, A, Milaneschi, Y, V. A. Million Veteran Program, O'Donnell, CJ, Wilson, OD, Gaziano, JM, Mishra, PP, Mohlke, KL, Mononen, N, Montgomery, GW, Mook-Kanamori, DO, Müller-Nurasyid, M, Nadkarni, GN, Nalls, MA, Nauck, M, Nikus, K, Ning, B, Nolte, IM, Noordam, R, O'Connell, JR, Olafsson, I, Padmanabhan, S, Penninx, BWJH, Perls, T, Peters, A, Pirastu, M, Pirastu, N, Pistis, G, Polasek, O, Ponte, B, Porteous, DJ, Poulain, T, Preuss, MH, Rabelink, TJ, Raffield, LM, Raitakari, OT, Rettig, R, Rheinberger, M, Rice, KM, Rizzi, F, Robino, A, Rudan, I, Krajcoviechova, A, Cifkova, R, Rueedi, R, Ruggiero, D, Ryan, KA, Saba, Y, Salvi, E, Schmidt, H, Schmidt, R, Shaffer, CM, Smith, AV, Smith, BH, Spracklen, CN, Strauch, K, Stumvoll, M, Sulem, P, Tajuddin, SM, Teren, A, Thiery, J, Thio, CHL, Thorsteinsdottir, U, Toniolo, D, Tönjes, A, Tremblay, J, Uitterlinden, AG, Vaccargiu, S, van der Harst, P, van Duijn, CM, Verweij, N, Völker, U, Vollenweider, P, Waeber, G, Waldenberger, M, Whitfield, JB, Wild, SH , Wilson, JF, Yang, Q, Zhang, W, Zonderman, AB, Bochud, M, Wilson, JG, Pendergrass, SA, Ho, K, Parsa, A, Pramstaller, PP, Psaty, BM, Böger, CA, Snieder, H, Butterworth, AS, Okada, Y, Edwards, TL, Stefansson, K, Susztak, K, Scholz, M, Heid, IM, Hung, AM, Teumer, A, Pattaro, C, Woodward, OM, Vitart, V & 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 - Coresh, Josef

AU - Corre, Tanguy

AU - Cusi, Daniele

AU - Sala, Cinzia Felicita

AU - de Borst, Martin H

AU - De Grandi, Alessandro

AU - de Mutsert, Renee

AU - de Vries, Aiko P. J.

AU - Delgado, Graciela

AU - Demirkan, Ayşe

AU - Devuyst, Olivier

AU - Dittrich, Katalin

AU - Eckardt, Kai-Uwe

AU - Ehret, Georg

AU - Endlich, Karlhans

AU - Evans, Michele K.

AU - Gansevoort, Ron T.

AU - Gasparini, Paolo

AU - Giedraitis, Vilmantas

AU - Gieger, Christian

AU - Girotto, Giorgia

AU - Gögele, Martin

AU - Gordon, Scott D.

AU - Gudbjartsson, Daniel F.

AU - Gudnason, Vilmundur

AU - German Chronic Kidney Disease Study

AU - Haller, Toomas

AU - Hamet, Pavel

AU - Harris, Tamara B.

AU - Hayward, Caroline

AU - Hicks, Andrew A

AU - Hofer, Edith

AU - Holm, Hilma

AU - Huang, Wei

AU - Hutri-Kähönen, Nina

AU - Hwang, Shih-Jen

AU - Arfan Ikram, M.

AU - Lewis, Raychel M.

AU - Ingelsson, Erik

AU - Jakobsdottir, Johanna

AU - Jonsdottir, Ingileif

AU - Jonsson, Helgi

AU - Joshi, Peter K

AU - Josyula, Navya Shilpa

AU - Jung, Bettina

AU - Kähönen, Mika

AU - Kamatani, Yoichiro

AU - Kanai, Masahiro

AU - Kerr, Shona M.

AU - Kiess, Wieland

AU - Kleber, Marcus E.

AU - Koenig, Wolfgang

AU - Kooner, Jaspal S.

AU - Körner, Antje

AU - Kovacs, Peter

AU - Krämer, Bernhard K.

AU - Kronenberg, Florian

AU - Kubo, Michiaki

AU - Kühnel, Brigitte

AU - La Bianca, Martina

AU - Lange, Leslie A.

AU - Lehne, Benjamin

AU - Lehtimäki, Terho

AU - LifeLines Cohort Study

AU - Liu, Jun

AU - Loeffler, Markus

AU - Loos, Ruth J. F.

AU - Lyytikäinen, Leo-Pekka

AU - Mägi, Reedik

AU - Mahajan, Anubha

AU - Martin, Nicholas G.

AU - März, Winfried

AU - Mascalzoni, Deborah

AU - Matsuda, Koichi

AU - Meisinger, Christa

AU - Meitinger, Thomas

AU - Metspalu, Andres

AU - Milaneschi, Yuri

AU - V. A. Million Veteran Program

AU - O'Donnell, Christopher J.

AU - Wilson, Otis D.

AU - Gaziano, J. Michael

AU - Mishra, Pashupati P.

AU - Mohlke, Karen L.

AU - Mononen, Nina

AU - Montgomery, Grant W.

AU - Mook-Kanamori, Dennis O.

AU - Müller-Nurasyid, Martina

AU - Nadkarni, Girish N.

AU - Nalls, Mike A.

AU - Nauck, Matthias

AU - Nikus, Kjell

AU - Ning, Boting

AU - Nolte, Ilja M.

AU - Noordam, Raymond

AU - O'Connell, Jeffrey R.

AU - Olafsson, Isleifur

AU - Padmanabhan, Sandosh

AU - Penninx, Brenda W. J. H.

AU - Perls, Thomas

AU - Peters, Annette

AU - Pirastu, Mario

AU - Pirastu, Nicola

AU - Pistis, Giorgio

AU - Polasek, Ozren

AU - Ponte, Belen

AU - Porteous, David J.

AU - Poulain, Tanja

AU - Preuss, Michael H.

AU - Rabelink, Ton J.

AU - Raffield, Laura M.

AU - Raitakari, Olli T.

AU - Rettig, Rainer

AU - Rheinberger, Myriam

AU - Rice, Kenneth M.

AU - Rizzi, Federica

AU - Robino, Antonietta

AU - Rudan, Igor

AU - Krajcoviechova, Alena

AU - Cifkova, Renata

AU - Rueedi, Rico

AU - Ruggiero, Daniela

AU - Ryan, Kathleen A.

AU - Saba, Yasaman

AU - Salvi, Erika

AU - Schmidt, Helena

AU - Schmidt, Reinhold

AU - Shaffer, Christian M.

AU - Smith, Albert V.

AU - Smith, Blair H.

AU - Spracklen, Cassandra N.

AU - Strauch, Konstantin

AU - Stumvoll, Michael

AU - Sulem, Patrick

AU - Tajuddin, Salman M.

AU - Teren, Andrej

AU - Thiery, Joachim

AU - Thio, Chris H. L.

AU - Thorsteinsdottir, Unnur

AU - Toniolo, Daniela

AU - Tönjes, Anke

AU - Tremblay, Johanne

AU - Uitterlinden, André G.

AU - Vaccargiu, Simona

AU - van der Harst, Pim

AU - van Duijn, Cornelia M.

AU - Verweij, Niek

AU - Völker, Uwe

AU - Vollenweider, Peter

AU - Waeber, Gerard

AU - Waldenberger, Melanie

AU - Whitfield, John B.

AU - Wild, Sarah H.

AU - Wilson, James F.

AU - Yang, Qiong

AU - Zhang, Weihua

AU - Zonderman, Alan B.

AU - Bochud, Murielle

AU - Wilson, James G.

AU - Pendergrass, Sarah A.

AU - Ho, Kevin

AU - Parsa, Afshin

AU - Pramstaller, Peter P.

AU - Psaty, Bruce M.

AU - Böger, Carsten A.

AU - Snieder, Harold

AU - Butterworth, Adam S.

AU - Okada, Yukinori

AU - Edwards, Todd L.

AU - Stefansson, Kari

AU - Susztak, Katalin

AU - Scholz, Markus

AU - Heid, Iris M.

AU - Hung, Adriana M.

AU - Teumer, Alexander

AU - Pattaro, Cristian

AU - Woodward, Owen M.

AU - Vitart, Veronique

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

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

Abstract / Description of output

Access to Document

Fingerprint

Cite this