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

A Tin; J Marten; VL Halperin Kuhns; Y Li; M Wuttke; H Kirsten; KB Sieber; C Qiu; M Gorski; Z Yu; A Giri; G Sveinbjornsson; M Li; AY Chu; A Hoppmann; LJ O’Connor; B Prins; T Nutile; D Noce; M Akiyama; M Cocca; S Ghasemi; PJ van der Most; K Horn; Y Xu; C Fuchsberger; S Sedaghat; S Afaq; N Amin; J Ärnlöv; SJL Bakker; N Bansal; D Baptista; S Bergmann; ML Biggs; G Biino; E Boerwinkle; EP Bottinger; TS Boutin; M Brumat; R Burkhardt; E Campana; A Campbell; H Campbell; RJ Carroll; E Catamo; JC Chambers; M Ciullo; MP Concas; J Coresh; T Corre; D Cusi; CF Sala; MH de Borst; A De Grandi; R de Mutsert; APJ de Vries; G Delgado; A Demirkan; O Devuyst; K Dittrich; K-U Eckardt; G Ehret; K Endlich; MK Evans; RT Gansevoort; P Gasparini; V Giedraitis; C Gieger; G Girotto; M Gögele; SD Gordon; DF Gudbjartsson; V Gudnason; T Haller; P Hamet; TB Harris; C Hayward; AA Hicks; E Hofer; H Holm; W Huang; N Hutri-Kähönen; S-J Hwang; MA Ikram; RM Lewis; E Ingelsson; J Jakobsdottir; I Jonsdottir; H Jonsson; PK Joshi; NS Josyula; B Jung; M Kähönen; Y Kamatani; M Kanai; SM Kerr; W Kiess; ME Kleber; W Koenig; JS Kooner; A Körner; P Kovacs; BK Krämer; F Kronenberg; M Kubo; B Kühnel; M La Bianca; LA Lange; B Lehne; T Lehtimäki; J Liu; M Loeffler; RJF Loos; L-P Lyytikäinen; R Magi; A Mahajan; NG Martin; W März; D Mascalzoni; K Matsuda; C Meisinger; T Meitinger; A Metspalu; Y Milaneschi; CJ O’Donnell; OD Wilson; JM Gaziano; PP Mishra; KL Mohlke; N Mononen; GW Montgomery; DO Mook-Kanamori; M Müller-Nurasyid; GN Nadkarni; MA Nalls; M Nauck; K Nikus; B Ning; IM Nolte; R Noordam; JR O’Connell; I Olafsson; S Padmanabhan; BWJH Penninx; T Perls; A Peters; M Pirastu; N Pirastu; G Pistis; O Polasek; B Ponte; DJ Porteous; T Poulain; MH Preuss; TJ Rabelink; LM Raffield; OT Raitakari; R Rettig; M Rheinberger; KM Rice; F Rizzi; A Robino; I Rudan; A Krajcoviechova; R Cifkova; R Rueedi; D Ruggiero; KA Ryan; Y Saba; E Salvi; H Schmidt; R Schmidt; CM Shaffer; AV Smith; BH Smith; CN Spracklen; K Strauch; M Stumvoll; P Sulem; SM Tajuddin; A Teren; J Thiery; CHL Thio; U Thorsteinsdottir; D Toniolo; A Tönjes; J Tremblay; AG Uitterlinden; S Vaccargiu; P van der Harst; CM van Duijn; N Verweij; U Völker; P Vollenweider; G Waeber; M Waldenberger; JB Whitfield; SH Wild; JF Wilson; Q Yang; W Zhang; AB Zonderman; M Bochud; JG Wilson; SA Pendergrass; K Ho; A Parsa; PP Pramstaller; BM Psaty; CA Böger; H Snieder; AS Butterworth; Y Okada; TL Edwards; K Stefansson; K Susztak; M Scholz; IM Heid; AM Hung; A Teumer; C Pattaro; OM Woodward; V Vitart; A Köttgen; German Chronic Kidney Disease Study; Lifelines Cohort Study; V. A. Million Veteran Program

doi:10.1038/s41588-019-0504-x

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

A Tin, J Marten, VL Halperin Kuhns, Y Li, M Wuttke, H Kirsten, KB Sieber, C Qiu, M Gorski, Z Yu, A Giri, G Sveinbjornsson, M Li, AY Chu, A Hoppmann, LJ O’Connor, B Prins, T Nutile, D Noce, M AkiyamaM Cocca, S Ghasemi, PJ van der Most, K Horn, Y Xu, C Fuchsberger, S Sedaghat, S Afaq, N Amin, J Ärnlöv, SJL Bakker, N Bansal, D Baptista, S Bergmann, ML Biggs, G Biino, E Boerwinkle, EP Bottinger, TS Boutin, M Brumat, R Burkhardt, E Campana, A Campbell, H Campbell, RJ Carroll, E Catamo, JC Chambers, M Ciullo, MP Concas, J Coresh, T Corre, D Cusi, CF Sala, MH de Borst, A De Grandi, R de Mutsert, APJ de Vries, G Delgado, A Demirkan, O Devuyst, K Dittrich, K-U Eckardt, G Ehret, K Endlich, MK Evans, RT Gansevoort, P Gasparini, V Giedraitis, C Gieger, G Girotto, M Gögele, SD Gordon, DF Gudbjartsson, V Gudnason, T Haller, P Hamet, TB Harris, C Hayward, AA Hicks, E Hofer, H Holm, W Huang, N Hutri-Kähönen, S-J Hwang, MA Ikram, RM Lewis, E Ingelsson, J Jakobsdottir, I Jonsdottir, H Jonsson, PK Joshi, NS Josyula, B Jung, M Kähönen, Y Kamatani, M Kanai, SM Kerr, W Kiess, ME Kleber, W Koenig, JS Kooner, A Körner, P Kovacs, BK Krämer, F Kronenberg, M Kubo, B Kühnel, M La Bianca, LA Lange, B Lehne, T Lehtimäki, J Liu, M Loeffler, RJF Loos, L-P Lyytikäinen, R Magi, A Mahajan, NG Martin, W März, D Mascalzoni, K Matsuda, C Meisinger, T Meitinger, A Metspalu, Y Milaneschi, CJ O’Donnell, OD Wilson, JM Gaziano, PP Mishra, KL Mohlke, N Mononen, GW Montgomery, DO Mook-Kanamori, M Müller-Nurasyid, GN Nadkarni, MA Nalls, M Nauck, K Nikus, B Ning, IM Nolte, R Noordam, JR O’Connell, I Olafsson, S Padmanabhan, BWJH Penninx, T Perls, A Peters, M Pirastu, N Pirastu, G Pistis, O Polasek, B Ponte, DJ Porteous, T Poulain, MH Preuss, TJ Rabelink, LM Raffield, OT Raitakari, R Rettig, M Rheinberger, KM Rice, F Rizzi, A Robino, I Rudan, A Krajcoviechova, R Cifkova, R Rueedi, D Ruggiero, KA Ryan, Y Saba, E Salvi, H Schmidt, R Schmidt, CM Shaffer, AV Smith, BH Smith, CN Spracklen, K Strauch, M Stumvoll, P Sulem, SM Tajuddin, A Teren, J Thiery, CHL Thio, U Thorsteinsdottir, D Toniolo, A Tönjes, J Tremblay, AG Uitterlinden, S Vaccargiu, P van der Harst, CM van Duijn, N Verweij, U Völker, P Vollenweider, G Waeber, M Waldenberger, JB Whitfield, SH Wild, JF Wilson, Q Yang, W Zhang, AB Zonderman, M Bochud, JG Wilson, SA Pendergrass, K Ho, A Parsa, PP Pramstaller, BM Psaty, CA Böger, H Snieder, AS Butterworth, Y Okada, TL Edwards, K Stefansson, K Susztak, M Scholz, IM Heid, AM Hung, A Teumer, C Pattaro, OM Woodward, V Vitart, A Köttgen, German Chronic Kidney Disease Study, Lifelines Cohort Study, V. A. Million Veteran Program

IRCCS Ospedale San Raffaele

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

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. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

Original language	English
Pages (from-to)	1459-1474
Number of pages	16
Journal	Nature Genetics
Volume	51
Issue number	10
DOIs	https://doi.org/10.1038/s41588-019-0504-x
Publication status	Published - 2019

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Cite this

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., ... Program, V. A. M. V. (2019). Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels: Nature Genetics. Nature Genetics, 51(10), 1459-1474. https://doi.org/10.1038/s41588-019-0504-x

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels : Nature Genetics. / 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; Haller, T; Hamet, P; Harris, TB; Hayward, C; Hicks, AA; Hofer, E; Holm, H; Huang, W; Hutri-Kähönen, N; Hwang, S-J; Ikram, MA; 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; Liu, J; Loeffler, M; Loos, RJF; Lyytikäinen, L-P; Magi, R; Mahajan, A; Martin, NG; März, W; Mascalzoni, D; Matsuda, K; Meisinger, C; Meitinger, T; Metspalu, A; Milaneschi, Y; 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; Study, German Chronic Kidney Disease; Study, Lifelines Cohort; Program, V. A. Million Veteran.

In: Nature Genetics, Vol. 51, No. 10, 2019, p. 1459-1474.

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

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, Haller, T, Hamet, P, Harris, TB, Hayward, C, Hicks, AA, Hofer, E, Holm, H, Huang, W, Hutri-Kähönen, N, Hwang, S-J, Ikram, MA, 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, Liu, J, Loeffler, M, Loos, RJF, Lyytikäinen, L-P, Magi, R, Mahajan, A, Martin, NG, März, W, Mascalzoni, D, Matsuda, K, Meisinger, C, Meitinger, T, Metspalu, A, Milaneschi, Y, 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, Study, GCKD, Study, LC & Program, VAMV 2019, 'Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels: Nature Genetics', Nature Genetics, vol. 51, no. 10, pp. 1459-1474. https://doi.org/10.1038/s41588-019-0504-x

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 ; Haller, T ; Hamet, P ; Harris, TB ; Hayward, C ; Hicks, AA ; Hofer, E ; Holm, H ; Huang, W ; Hutri-Kähönen, N ; Hwang, S-J ; Ikram, MA ; 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 ; Liu, J ; Loeffler, M ; Loos, RJF ; Lyytikäinen, L-P ; Magi, R ; Mahajan, A ; Martin, NG ; März, W ; Mascalzoni, D ; Matsuda, K ; Meisinger, C ; Meitinger, T ; Metspalu, A ; Milaneschi, Y ; 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 ; Study, German Chronic Kidney Disease ; Study, Lifelines Cohort ; Program, V. A. Million Veteran. / Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels : Nature Genetics. In: Nature Genetics. 2019 ; Vol. 51, No. 10. pp. 1459-1474.

@article{eacf71d0541d404583cc362df2a85681,

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

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. {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",

author = "A Tin and J Marten and {Halperin Kuhns}, VL and Y Li and M Wuttke and H Kirsten and KB Sieber and C Qiu and M Gorski and Z Yu and A Giri and G Sveinbjornsson and M Li and AY Chu and A Hoppmann and LJ O{\textquoteright}Connor and B Prins and T Nutile and D Noce and M Akiyama and M Cocca and S Ghasemi and {van der Most}, PJ and K Horn and Y Xu and C Fuchsberger and S Sedaghat and S Afaq and N Amin and J {\"A}rnl{\"o}v and SJL Bakker and N Bansal and D Baptista and S Bergmann and ML Biggs and G Biino and E Boerwinkle and EP Bottinger and TS Boutin and M Brumat and R Burkhardt and E Campana and A Campbell and H Campbell and RJ Carroll and E Catamo and JC Chambers and M Ciullo and MP Concas and J Coresh and T Corre and D Cusi and CF Sala and {de Borst}, MH and {De Grandi}, A and {de Mutsert}, R and {de Vries}, APJ and G Delgado and A Demirkan and O Devuyst and K Dittrich and K-U Eckardt and G Ehret and K Endlich and MK Evans and RT Gansevoort and P Gasparini and V Giedraitis and C Gieger and G Girotto and M G{\"o}gele and SD Gordon and DF Gudbjartsson and V Gudnason and T Haller and P Hamet and TB Harris and C Hayward and AA Hicks and E Hofer and H Holm and W Huang and N Hutri-K{\"a}h{\"o}nen and S-J Hwang and MA Ikram and RM Lewis and E Ingelsson and J Jakobsdottir and I Jonsdottir and H Jonsson and PK Joshi and NS Josyula and B Jung and M K{\"a}h{\"o}nen and Y Kamatani and M Kanai and SM Kerr and W Kiess and ME Kleber and W Koenig and JS Kooner and A K{\"o}rner and P Kovacs and BK Kr{\"a}mer and F Kronenberg and M Kubo and B K{\"u}hnel and {La Bianca}, M and LA Lange and B Lehne and T Lehtim{\"a}ki and J Liu and M Loeffler and RJF Loos and L-P Lyytik{\"a}inen and R Magi and A Mahajan and NG Martin and W M{\"a}rz and D Mascalzoni and K Matsuda and C Meisinger and T Meitinger and A Metspalu and Y Milaneschi and CJ O{\textquoteright}Donnell and OD Wilson and JM Gaziano and PP Mishra and KL Mohlke and N Mononen and GW Montgomery and DO Mook-Kanamori and M M{\"u}ller-Nurasyid and GN Nadkarni and MA Nalls and M Nauck and K Nikus and B Ning and IM Nolte and R Noordam and JR O{\textquoteright}Connell and I Olafsson and S Padmanabhan and BWJH Penninx and T Perls and A Peters and M Pirastu and N Pirastu and G Pistis and O Polasek and B Ponte and DJ Porteous and T Poulain and MH Preuss and TJ Rabelink and LM Raffield and OT Raitakari and R Rettig and M Rheinberger and KM Rice and F Rizzi and A Robino and I Rudan and A Krajcoviechova and R Cifkova and R Rueedi and D Ruggiero and KA Ryan and Y Saba and E Salvi and H Schmidt and R Schmidt and CM Shaffer and AV Smith and BH Smith and CN Spracklen and K Strauch and M Stumvoll and P Sulem and SM Tajuddin and A Teren and J Thiery and CHL Thio and U Thorsteinsdottir and D Toniolo and A T{\"o}njes and J Tremblay and AG Uitterlinden and S Vaccargiu and {van der Harst}, P and {van Duijn}, CM and N Verweij and U V{\"o}lker and P Vollenweider and G Waeber and M Waldenberger and JB Whitfield and SH Wild and JF Wilson and Q Yang and W Zhang and AB Zonderman and M Bochud and JG Wilson and SA Pendergrass and K Ho and A Parsa and PP Pramstaller and BM Psaty and CA B{\"o}ger and H Snieder and AS Butterworth and Y Okada and TL Edwards and K Stefansson and K Susztak and M Scholz and IM Heid and AM Hung and A Teumer and C Pattaro and OM Woodward and V Vitart and A K{\"o}ttgen and Study, {German Chronic Kidney Disease} and Study, {Lifelines Cohort} and Program, {V. A. Million Veteran}",

year = "2019",

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",

}

TY - JOUR

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

T2 - Nature Genetics

AU - Tin, A

AU - Marten, J

AU - Halperin Kuhns, VL

AU - Li, Y

AU - Wuttke, M

AU - Kirsten, H

AU - Sieber, KB

AU - Qiu, C

AU - Gorski, M

AU - Yu, Z

AU - Giri, A

AU - Sveinbjornsson, G

AU - Li, M

AU - Chu, AY

AU - Hoppmann, A

AU - O’Connor, LJ

AU - Prins, B

AU - Nutile, T

AU - Noce, D

AU - Akiyama, M

AU - Cocca, M

AU - Ghasemi, S

AU - van der Most, PJ

AU - Horn, K

AU - Xu, Y

AU - Fuchsberger, C

AU - Sedaghat, S

AU - Afaq, S

AU - Amin, N

AU - Ärnlöv, J

AU - Bakker, SJL

AU - Bansal, N

AU - Baptista, D

AU - Bergmann, S

AU - Biggs, ML

AU - Biino, G

AU - Boerwinkle, E

AU - Bottinger, EP

AU - Boutin, TS

AU - Brumat, M

AU - Burkhardt, R

AU - Campana, E

AU - Campbell, A

AU - Campbell, H

AU - Carroll, RJ

AU - Catamo, E

AU - Chambers, JC

AU - Ciullo, M

AU - Concas, MP

AU - Coresh, J

AU - Corre, T

AU - Cusi, D

AU - Sala, CF

AU - de Borst, MH

AU - De Grandi, A

AU - de Mutsert, R

AU - de Vries, APJ

AU - Delgado, G

AU - Demirkan, A

AU - Devuyst, O

AU - Dittrich, K

AU - Eckardt, K-U

AU - Ehret, G

AU - Endlich, K

AU - Evans, MK

AU - Gansevoort, RT

AU - Gasparini, P

AU - Giedraitis, V

AU - Gieger, C

AU - Girotto, G

AU - Gögele, M

AU - Gordon, SD

AU - Gudbjartsson, DF

AU - Gudnason, V

AU - Haller, T

AU - Hamet, P

AU - Harris, TB

AU - Hayward, C

AU - Hicks, AA

AU - Hofer, E

AU - Holm, H

AU - Huang, W

AU - Hutri-Kähönen, N

AU - Hwang, S-J

AU - Ikram, MA

AU - Lewis, RM

AU - Ingelsson, E

AU - Jakobsdottir, J

AU - Jonsdottir, I

AU - Jonsson, H

AU - Joshi, PK

AU - Josyula, NS

AU - Jung, B

AU - Kähönen, M

AU - Kamatani, Y

AU - Kanai, M

AU - Kerr, SM

AU - Kiess, W

AU - Kleber, ME

AU - Koenig, W

AU - Kooner, JS

AU - Körner, A

AU - Kovacs, P

AU - Krämer, BK

AU - Kronenberg, F

AU - Kubo, M

AU - Kühnel, B

AU - La Bianca, M

AU - Lange, LA

AU - Lehne, B

AU - Lehtimäki, T

AU - Liu, J

AU - Loeffler, M

AU - Loos, RJF

AU - Lyytikäinen, L-P

AU - Magi, R

AU - Mahajan, A

AU - Martin, NG

AU - März, W

AU - Mascalzoni, D

AU - Matsuda, K

AU - Meisinger, C

AU - Meitinger, T

AU - Metspalu, A

AU - Milaneschi, Y

AU - O’Donnell, CJ

AU - Wilson, OD

AU - Gaziano, JM

AU - Mishra, PP

AU - Mohlke, KL

AU - Mononen, N

AU - Montgomery, GW

AU - Mook-Kanamori, DO

AU - Müller-Nurasyid, M

AU - Nadkarni, GN

AU - Nalls, MA

AU - Nauck, M

AU - Nikus, K

AU - Ning, B

AU - Nolte, IM

AU - Noordam, R

AU - O’Connell, JR

AU - Olafsson, I

AU - Padmanabhan, S

AU - Penninx, BWJH

AU - Perls, T

AU - Peters, A

AU - Pirastu, M

AU - Pirastu, N

AU - Pistis, G

AU - Polasek, O

AU - Ponte, B

AU - Porteous, DJ

AU - Poulain, T

AU - Preuss, MH

AU - Rabelink, TJ

AU - Raffield, LM

AU - Raitakari, OT

AU - Rettig, R

AU - Rheinberger, M

AU - Rice, KM

AU - Rizzi, F

AU - Robino, A

AU - Rudan, I

AU - Krajcoviechova, A

AU - Cifkova, R

AU - Rueedi, R

AU - Ruggiero, D

AU - Ryan, KA

AU - Saba, Y

AU - Salvi, E

AU - Schmidt, H

AU - Schmidt, R

AU - Shaffer, CM

AU - Smith, AV

AU - Smith, BH

AU - Spracklen, CN

AU - Strauch, K

AU - Stumvoll, M

AU - Sulem, P

AU - Tajuddin, SM

AU - Teren, A

AU - Thiery, J

AU - Thio, CHL

AU - Thorsteinsdottir, U

AU - Toniolo, D

AU - Tönjes, A

AU - Tremblay, J

AU - Uitterlinden, AG

AU - Vaccargiu, S

AU - van der Harst, P

AU - van Duijn, CM

AU - Verweij, N

AU - Völker, U

AU - Vollenweider, P

AU - Waeber, G

AU - Waldenberger, M

AU - Whitfield, JB

AU - Wild, SH

AU - Wilson, JF

AU - Yang, Q

AU - Zhang, W

AU - Zonderman, AB

AU - Bochud, M

AU - Wilson, JG

AU - Pendergrass, SA

AU - Ho, K

AU - Parsa, A

AU - Pramstaller, PP

AU - Psaty, BM

AU - Böger, CA

AU - Snieder, H

AU - Butterworth, AS

AU - Okada, Y

AU - Edwards, TL

AU - Stefansson, K

AU - Susztak, K

AU - Scholz, M

AU - Heid, IM

AU - Hung, AM

AU - Teumer, A

AU - Pattaro, C

AU - Woodward, OM

AU - Vitart, V

AU - Köttgen, A

AU - Study, German Chronic Kidney Disease

AU - Study, Lifelines Cohort

AU - Program, V. A. Million Veteran

PY - 2019

Y1 - 2019

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. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

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. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

U2 - 10.1038/s41588-019-0504-x

DO - 10.1038/s41588-019-0504-x

M3 - Article

VL - 51

SP - 1459

EP - 1474

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 10

ER -

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

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