Abstract
Original language | English |
---|---|
Pages (from-to) | 1459-1474 |
Number of pages | 16 |
Journal | Nature Genetics |
Volume | 51 |
Issue number | 10 |
DOIs | |
Publication status | Published - 2019 |
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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
}
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 -