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

Tin, Adrienne; Marten, Jonathan; Halperin Kuhns, Victoria L.; Li, Yong; Wuttke, Matthias; Kirsten, Holger; Sieber, Karsten B.; Qiu, Chengxiang; Gorski, Mathias; Yu, Zhi; Giri, Ayush; Sveinbjornsson, Gardar; Li, Man; Chu, Audrey Y.; Hoppmann, Anselm; O'Connor, Luke; Prins, Bram; Nutile, Teresa; Noce, Damia; Akiyama, Masato; Cocca, Massimiliano; Ghasemi, Sahar; van der Most, Peter J.; Horn, Katrin; Xu, Yizhe; Fuchsberger, Christian; Sedaghat, Sanaz; Afaq, Saima; Amin, Najaf; Ärnlöv, Johan; Bakker, Stephan J. L.; Bansal, Nisha; Baptista, Daniela; Bergmann, Sven; Biggs, Mary L.; Biino, Ginevra; Boerwinkle, Eric; Bottinger, Erwin P.; Boutin, Thibaud S.; Brumat, Marco; Burkhardt, Ralph; Campana, Eric; Campbell, Archie; Campbell, Harry; Carroll, Robert J.; Catamo, Eulalia; Chambers, John C.; Ciullo, Marina; Concas, Maria Pina; Coresh, Josef; Corre, Tanguy; Cusi, Daniele; Felicita, Sala Cinzia; de Borst, Martin H.; De Grandi, Alessandro; de Mutsert, Renée; de Vries, Aiko P. J.; Delgado, Graciela; Demirkan, Ayşe; Devuyst, Olivier; Dittrich, Katalin; Eckardt, Kai-Uwe; Ehret, Georg; Endlich, Karlhans; Evans, Michele K.; Gansevoort, Ron T.; Gasparini, Paolo; Giedraitis, Vilmantas; Gieger, Christian; Girotto, Giorgia; Gögele, Martin; Gordon, Scott D.; Gudbjartsson, Daniel F.; Gudnason, Vilmundur; Haller, Toomas; Hamet, Pavel; Harris, Tamara B.; Hayward, Caroline; Hicks, Andrew A.; Hofer, Edith; Holm, Hilma; Huang, Wei; Hutri-Kähönen, Nina; Hwang, Shih-Jen; Ikram, M. Arfan; Lewis, Raychel M.; Ingelsson, Erik; Jakobsdottir, Johanna; Jonsdottir, Ingileif; Jonsson, Helgi; Joshi, Peter K.; Josyula, Navya Shilpa; Jung, Bettina; Kähönen, Mika; Kamatani, Yoichiro; Kanai, Masahiro; Kerr, Shona M.; Kiess, Wieland; Kleber, Marcus E.; Koenig, Wolfgang; Kooner, Jaspal S.; Körner, Antje; Kovacs, Peter; Krämer, Bernhard K.; Kronenberg, Florian; Kubo, Michiaki; Kühnel, Brigitte; La Bianca, Martina; Lange, Leslie A.; Lehne, Benjamin; Lehtimäki, Terho; Liu, Jun; Loeffler, Markus; Loos, Ruth J. F.; Lyytikäinen, Leo-Pekka; Magi, Reedik; Mahajan, Anubha; Martin, Nicholas G.; März, Winfried; Mascalzoni, Deborah; Matsuda, Koichi; Meisinger, Christa; Meitinger, Thomas; Metspalu, Andres; Milaneschi, Yuri; O'Donnell, Christopher; Wilson, Otis D.; Gaziano, John; Mishra, Pashupati P.; Mohlke, Karen L.; Mononen, Nina; Montgomery, Grant W.; Mook-Kanamori, Dennis O.; Müller-Nurasyid, Martina; Nadkarni, Girish N.; Nalls, Mike A.; Nauck, Matthias; Nikus, Kjell; Ning, Boting; Nolte, Ilja M.; Noordam, Raymond; O’Connell, Jeffrey R.; Olafsson, Isleifur; Padmanabhan, Sandosh; Penninx, Brenda W. J. H.; Perls, Thomas; Peters, Annette; Pirastu, Mario; Pirastu, Nicola; Pistis, Giorgio; Polasek, Ozren; Ponte, Belen; Porteous, David J.; Poulain, Tanja; Preuss, Michael H.; Rabelink, Ton J.; Raffield, Laura M.; Raitakari, Olli T.; Rettig, Rainer; Rheinberger, Myriam; Rice, Kenneth M.; Rizzi, Federica; Robino, Antonietta; Rudan, Igor; Krajcoviechova, Alena; Cifkova, Renata; Rueedi, Rico; Ruggiero, Daniela; Ryan, Kathleen A.; Saba, Yasaman; Salvi, Erika; Schmidt, Helena; Schmidt, Reinhold; Shaffer, Christian M.; Smith, Albert V.; Smith, Blair H.; Spracklen, Cassandra N.; Strauch, Konstantin; Stumvoll, Michael; Sulem, Patrick; Tajuddin, Salman M.; Teren, Andrej; Thiery, Joachim; Thio, Chris H. L.; Thorsteinsdottir, Unnur; Toniolo, Daniela; Tönjes, Anke; Tremblay, Johanne; Uitterlinden, André G.; Vaccargiu, Simona; van der Harst, Pim; van Duijn, Cornelia M.; Verweij, Niek; Völker, Uwe; Vollenweider, Peter; Waeber, Gerard; Waldenberger, Melanie; Whitfield, John B.; Wild, Sarah H.; Wilson, James F.; Yang, Qiong; Zhang, Weihua; Zonderman, Alan B.; Bochud, Murielle; Wilson, James G.; Pendergrass, Sarah A.; Ho, Kevin; Parsa, Afshin; Pramstaller, Peter P.; Psaty, Bruce M.; Böger, Carsten A.; Snieder, Harold; Butterworth, Adam S.; Okada, Yukinori; Edwards, Todd L.; Stefansson, Kari; Susztak, Katalin; Scholz, Markus; Heid, Iris M.; Hung, Adriana M.; Teumer, Alexander; Pattaro, Cristian; Woodward, Owen M.; Vitart, Veronique; Köttgen, Anna

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Author

Tin, Adrienne

Marten, Jonathan

Halperin Kuhns, Victoria L.

Li, Yong

Wuttke, Matthias

Kirsten, Holger

Sieber, Karsten B.

Qiu, Chengxiang

Gorski, Mathias

Yu, Zhi

Giri, Ayush

Sveinbjornsson, Gardar

Li, Man

Chu, Audrey Y.

Hoppmann, Anselm

O'Connor, Luke HARVARD

Prins, Bram

Nutile, Teresa

Noce, Damia

Akiyama, Masato

Cocca, Massimiliano

Ghasemi, Sahar

van der Most, Peter J.

Horn, Katrin

Xu, Yizhe

Fuchsberger, Christian

Sedaghat, Sanaz

Afaq, Saima

Amin, Najaf

Ärnlöv, Johan

Bakker, Stephan J. L.

Bansal, Nisha

Baptista, Daniela

Bergmann, Sven

Biggs, Mary L.

Biino, Ginevra

Boerwinkle, Eric

Bottinger, Erwin P.

Boutin, Thibaud S.

Brumat, Marco

Burkhardt, Ralph

Campana, Eric

Campbell, Archie

Campbell, Harry

Carroll, Robert J.

Catamo, Eulalia

Chambers, John C.

Ciullo, Marina

Concas, Maria Pina

Coresh, Josef

Corre, Tanguy

Cusi, Daniele

Felicita, Sala Cinzia

de Borst, Martin H.

De Grandi, Alessandro

de Mutsert, Renée

de Vries, Aiko P. J.

Delgado, Graciela

Demirkan, Ayşe

Devuyst, Olivier

Dittrich, Katalin

Eckardt, Kai-Uwe

Ehret, Georg

Endlich, Karlhans

Evans, Michele K.

Gansevoort, Ron T.

Gasparini, Paolo

Giedraitis, Vilmantas

Gieger, Christian

Girotto, Giorgia

Gögele, Martin

Gordon, Scott D.

Gudbjartsson, Daniel F.

Gudnason, Vilmundur

Haller, Toomas

Hamet, Pavel

Harris, Tamara B.

Hayward, Caroline

Hicks, Andrew A.

Hofer, Edith

Holm, Hilma

Huang, Wei

Hutri-Kähönen, Nina

Hwang, Shih-Jen

Ikram, M. Arfan

Lewis, Raychel M.

Ingelsson, Erik

Jakobsdottir, Johanna

Jonsdottir, Ingileif

Jonsson, Helgi

Joshi, Peter K.

Josyula, Navya Shilpa

Jung, Bettina

Kähönen, Mika

Kamatani, Yoichiro

Kanai, Masahiro HARVARD

Kerr, Shona M.

Kiess, Wieland

Kleber, Marcus E.

Koenig, Wolfgang

Kooner, Jaspal S.

Körner, Antje

Kovacs, Peter

Krämer, Bernhard K.

Kronenberg, Florian

Kubo, Michiaki

Kühnel, Brigitte

La Bianca, Martina

Lange, Leslie A.

Lehne, Benjamin

Lehtimäki, Terho

Liu, Jun

Loeffler, Markus

Loos, Ruth J. F.

Lyytikäinen, Leo-Pekka

Magi, Reedik

Mahajan, Anubha

Martin, Nicholas G.

März, Winfried

Mascalzoni, Deborah

Matsuda, Koichi

Meisinger, Christa

Meitinger, Thomas

Metspalu, Andres

Milaneschi, Yuri

O'Donnell, Christopher HARVARD

Wilson, Otis D.

Gaziano, John HARVARD

Mishra, Pashupati P.

Mohlke, Karen L.

Mononen, Nina

Montgomery, Grant W.

Mook-Kanamori, Dennis O.

Müller-Nurasyid, Martina

Nadkarni, Girish N.

Nalls, Mike A.

Nauck, Matthias

Nikus, Kjell

Ning, Boting

Nolte, Ilja M.

Noordam, Raymond

O’Connell, Jeffrey R.

Olafsson, Isleifur

Padmanabhan, Sandosh

Penninx, Brenda W. J. H.

Perls, Thomas

Peters, Annette

Pirastu, Mario

Pirastu, Nicola

Pistis, Giorgio

Polasek, Ozren

Ponte, Belen

Porteous, David J.

Poulain, Tanja

Preuss, Michael H.

Rabelink, Ton J.

Raffield, Laura M.

Raitakari, Olli T.

Rettig, Rainer

Rheinberger, Myriam

Rice, Kenneth M.

Rizzi, Federica

Robino, Antonietta

Rudan, Igor

Krajcoviechova, Alena

Cifkova, Renata

Rueedi, Rico

Ruggiero, Daniela

Ryan, Kathleen A.

Saba, Yasaman

Salvi, Erika

Schmidt, Helena

Schmidt, Reinhold

Shaffer, Christian M.

Smith, Albert V.

Smith, Blair H.

Spracklen, Cassandra N.

Strauch, Konstantin

Stumvoll, Michael

Sulem, Patrick

Tajuddin, Salman M.

Teren, Andrej

Thiery, Joachim

Thio, Chris H. L.

Thorsteinsdottir, Unnur

Toniolo, Daniela

Tönjes, Anke

Tremblay, Johanne

Uitterlinden, André G.

Vaccargiu, Simona

van der Harst, Pim

van Duijn, Cornelia M.

Verweij, Niek

Völker, Uwe

Vollenweider, Peter

Waeber, Gerard

Waldenberger, Melanie

Whitfield, John B.

Wild, Sarah H.

Wilson, James F.

Yang, Qiong

Zhang, Weihua

Zonderman, Alan B.

Bochud, Murielle

Wilson, James G.

Pendergrass, Sarah A.

Ho, Kevin

Parsa, Afshin

Pramstaller, Peter P.

Psaty, Bruce M.

Böger, Carsten A.

Snieder, Harold

Butterworth, Adam S.

Okada, Yukinori

Edwards, Todd L.

Stefansson, Kari

Susztak, Katalin

Scholz, Markus

Heid, Iris M.

Hung, Adriana M.

Teumer, Alexander

Pattaro, Cristian

Woodward, Owen M.

Vitart, Veronique

Köttgen, Anna

Published Version

https://doi.org/10.1038/s41588-019-0504-x

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Citation

Tin, Adrienne, Jonathan Marten, Victoria L. Halperin Kuhns, Yong Li, Matthias Wuttke, Holger Kirsten, Karsten B. Sieber et al. "Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels." Nat Genet 51, no. 10 (2019): 1459-1474. DOI: 10.1038/s41588-019-0504-x

Abstract

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