Genome-wide association analyses identify 18 new loci associated with serum urate concentrations

Anna Köttgen; Eva Albrecht; Alexander Teumer; Veronique Vitart; Jan Krumsiek; Claudia Hundertmark; Giorgio Pistis; Daniela Ruggiero; Conall M O'Seaghdha; Toomas Haller; Qiong Yang; Toshiko Tanaka; Andrew D Johnson; Zoltán Kutalik; Albert V Smith; Julia Shi; Maksim Struchalin; Rita P S Middelberg; Morris J Brown; Angelo L Gaffo; Nicola Pirastu; Guo Li; Caroline Hayward; Tatijana Zemunik; Jennifer Huffman; Loic Yengo; Jing Hua Zhao; Ayse Demirkan; Mary F Feitosa; Xuan Liu; Giovanni Malerba; Lorna M Lopez; Pim van der Harst; Xinzhong Li; Marcus E Kleber; Andrew A Hicks; Ilja M Nolte; Asa Johansson; Federico Murgia; Sarah H Wild; Stephan J L Bakker; John F Peden; Abbas Dehghan; Maristella Steri; Albert Tenesa; Vasiliki Lagou; Perttu Salo; Massimo Mangino; Lynda M Rose; Alan J Gow; LifeLines Cohort Study; CARDIoGRAM Consortium; DIAGRAM Consortium; ICBP Consortium; MAGIC Consortium

doi:10.1038/ng.2500

Genome-wide association analyses identify 18 new loci associated with serum urate concentrations

Anna Köttgen, Eva Albrecht, Alexander Teumer, Veronique Vitart, Jan Krumsiek, Claudia Hundertmark, Giorgio Pistis, Daniela Ruggiero, Conall M O'Seaghdha, Toomas Haller, Qiong Yang, Toshiko Tanaka, Andrew D Johnson, Zoltán Kutalik, Albert V Smith, Julia Shi, Maksim Struchalin, Rita P S Middelberg, Morris J Brown, Angelo L GaffoNicola Pirastu, Guo Li, Caroline Hayward, Tatijana Zemunik, Jennifer Huffman, Loic Yengo, Jing Hua Zhao, Ayse Demirkan, Mary F Feitosa, Xuan Liu, Giovanni Malerba, Lorna M Lopez, Pim van der Harst, Xinzhong Li, Marcus E Kleber, Andrew A Hicks, Ilja M Nolte, Asa Johansson, Federico Murgia, Sarah H Wild, Stephan J L Bakker, John F Peden, Abbas Dehghan, Maristella Steri, Albert Tenesa, Vasiliki Lagou, Perttu Salo, Massimo Mangino, Lynda M Rose, Alan J Gow, LifeLines Cohort Study, CARDIoGRAM Consortium, DIAGRAM Consortium, ICBP Consortium, MAGIC Consortium

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Abstract

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

Original language	English
Pages (from-to)	145-154
Number of pages	10
Journal	Nature Genetics
Volume	45
Issue number	2
DOIs	https://doi.org/10.1038/ng.2500
Publication status	Published - Feb 2013

Keywords

Uric Acid
Polymorphism, Single Nucleotide
Analysis of Variance
Genetic Loci
Gene Frequency
Humans
European Continental Ancestry Group
Glucose
Inhibins
Signal Transduction
Gout
Genome-Wide Association Study

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Köttgen, A., Albrecht, E., Teumer, A., Vitart, V., Krumsiek, J., Hundertmark, C., Pistis, G., Ruggiero, D., O'Seaghdha, C. M., Haller, T., Yang, Q., Tanaka, T., Johnson, A. D., Kutalik, Z., Smith, A. V., Shi, J., Struchalin, M., Middelberg, R. P. S., Brown, M. J., ... MAGIC Consortium (2013). Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nature Genetics, 45(2), 145-154. https://doi.org/10.1038/ng.2500

@article{88b857cfe1134d948ab624d6ff618650,

title = "Genome-wide association analyses identify 18 new loci associated with serum urate concentrations",

abstract = "Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.",

keywords = "Uric Acid, Polymorphism, Single Nucleotide, Analysis of Variance, Genetic Loci, Gene Frequency, Humans, European Continental Ancestry Group, Glucose, Inhibins, Signal Transduction, Gout, Genome-Wide Association Study",

author = "Anna K{\"o}ttgen and Eva Albrecht and Alexander Teumer and Veronique Vitart and Jan Krumsiek and Claudia Hundertmark and Giorgio Pistis and Daniela Ruggiero and O'Seaghdha, {Conall M} and Toomas Haller and Qiong Yang and Toshiko Tanaka and Johnson, {Andrew D} and Zolt{\'a}n Kutalik and Smith, {Albert V} and Julia Shi and Maksim Struchalin and Middelberg, {Rita P S} and Brown, {Morris J} and Gaffo, {Angelo L} and Nicola Pirastu and Guo Li and Caroline Hayward and Tatijana Zemunik and Jennifer Huffman and Loic Yengo and Zhao, {Jing Hua} and Ayse Demirkan and Feitosa, {Mary F} and Xuan Liu and Giovanni Malerba and Lopez, {Lorna M} and {van der Harst}, Pim and Xinzhong Li and Kleber, {Marcus E} and Hicks, {Andrew A} and Nolte, {Ilja M} and Asa Johansson and Federico Murgia and Wild, {Sarah H} and Bakker, {Stephan J L} and Peden, {John F} and Abbas Dehghan and Maristella Steri and Albert Tenesa and Vasiliki Lagou and Perttu Salo and Massimo Mangino and Rose, {Lynda M} and Gow, {Alan J} and {LifeLines Cohort Study} and {CARDIoGRAM Consortium} and {DIAGRAM Consortium} and {ICBP Consortium} and {MAGIC Consortium}",

year = "2013",

month = feb,

doi = "10.1038/ng.2500",

language = "English",

volume = "45",

pages = "145--154",

journal = "Nature Genetics",

issn = "1546-1718",

publisher = "Nature Research",

number = "2",

}

Köttgen, A, Albrecht, E, Teumer, A, Vitart, V, Krumsiek, J, Hundertmark, C, Pistis, G, Ruggiero, D, O'Seaghdha, CM, Haller, T, Yang, Q, Tanaka, T, Johnson, AD, Kutalik, Z, Smith, AV, Shi, J, Struchalin, M, Middelberg, RPS, Brown, MJ, Gaffo, AL, Pirastu, N, Li, G, Hayward, C, Zemunik, T, Huffman, J, Yengo, L, Zhao, JH, Demirkan, A, Feitosa, MF, Liu, X, Malerba, G, Lopez, LM, van der Harst, P, Li, X, Kleber, ME, Hicks, AA, Nolte, IM, Johansson, A, Murgia, F, Wild, SH, Bakker, SJL, Peden, JF, Dehghan, A, Steri, M, Tenesa, A, Lagou, V, Salo, P, Mangino, M, Rose, LM, Gow, AJ, LifeLines Cohort Study, CARDIoGRAM Consortium, DIAGRAM Consortium, ICBP Consortium & MAGIC Consortium 2013, 'Genome-wide association analyses identify 18 new loci associated with serum urate concentrations', Nature Genetics, vol. 45, no. 2, pp. 145-154. https://doi.org/10.1038/ng.2500

TY - JOUR

T1 - Genome-wide association analyses identify 18 new loci associated with serum urate concentrations

AU - Köttgen, Anna

AU - Albrecht, Eva

AU - Teumer, Alexander

AU - Vitart, Veronique

AU - Krumsiek, Jan

AU - Hundertmark, Claudia

AU - Pistis, Giorgio

AU - Ruggiero, Daniela

AU - O'Seaghdha, Conall M

AU - Haller, Toomas

AU - Yang, Qiong

AU - Tanaka, Toshiko

AU - Johnson, Andrew D

AU - Kutalik, Zoltán

AU - Smith, Albert V

AU - Shi, Julia

AU - Struchalin, Maksim

AU - Middelberg, Rita P S

AU - Brown, Morris J

AU - Gaffo, Angelo L

AU - Pirastu, Nicola

AU - Li, Guo

AU - Hayward, Caroline

AU - Zemunik, Tatijana

AU - Huffman, Jennifer

AU - Yengo, Loic

AU - Zhao, Jing Hua

AU - Demirkan, Ayse

AU - Feitosa, Mary F

AU - Liu, Xuan

AU - Malerba, Giovanni

AU - Lopez, Lorna M

AU - van der Harst, Pim

AU - Li, Xinzhong

AU - Kleber, Marcus E

AU - Hicks, Andrew A

AU - Nolte, Ilja M

AU - Johansson, Asa

AU - Murgia, Federico

AU - Wild, Sarah H

AU - Bakker, Stephan J L

AU - Peden, John F

AU - Dehghan, Abbas

AU - Steri, Maristella

AU - Tenesa, Albert

AU - Lagou, Vasiliki

AU - Salo, Perttu

AU - Mangino, Massimo

AU - Rose, Lynda M

AU - Gow, Alan J

AU - LifeLines Cohort Study

AU - CARDIoGRAM Consortium

AU - DIAGRAM Consortium

AU - ICBP Consortium

AU - MAGIC Consortium

PY - 2013/2

Y1 - 2013/2

N2 - Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

AB - Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

KW - Uric Acid

KW - Polymorphism, Single Nucleotide

KW - Analysis of Variance

KW - Genetic Loci

KW - Gene Frequency

KW - Humans

KW - European Continental Ancestry Group

KW - Glucose

KW - Inhibins

KW - Signal Transduction

KW - Gout

KW - Genome-Wide Association Study

U2 - 10.1038/ng.2500

DO - 10.1038/ng.2500

M3 - Article

C2 - 23263486

SN - 1546-1718

VL - 45

SP - 145

EP - 154

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

Genome-wide association analyses identify 18 new loci associated with serum urate concentrations

Abstract

Keywords

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