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

LifeLines Cohort Study; 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; Sarah H Wild; Albert Tenesa; Pau Navarro; Nicholas Hastie; Gail Davies; Alan J Gow; James F Wilson; Susan M Farrington; Evropi Theodoratou; Ozren Polasek; Harry Campbell; Igor Rudan; Ian J Deary; Alan F Wright; Malcolm G Dunlop

doi:10.1038/ng.2500

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

LifeLines Cohort Study, 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 BrownAngelo 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, Sarah H Wild, Albert Tenesa, Pau Navarro, Nicholas Hastie, Gail Davies, Alan J Gow, James F Wilson, Susan M Farrington, Evropi Theodoratou, Ozren Polasek, Harry Campbell, Igor Rudan, Ian J Deary, Alan F Wright, Malcolm G Dunlop

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

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

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10.1038/ng.2500

Genome-wide association analyses identify 18 new loci associated with serum urate concentrations
Published in final edited form as: Nat Genet. 2013 February ; 45(2): 145–154. doi:10.1038/ng.2500.
Accepted author manuscript, 1.24 MB

http://www.nature.com/ng/journal/v45/n2/full/ng.2500.html

Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.
Maclullich, A. (Principal Investigator)
1/09/13 → 31/08/19
Project: Research
RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.
Deary, I. (Principal Investigator), Gale, C. (Co-investigator), Holmes, M. (Co-investigator), Logie, P. (Co-investigator), Maclullich, A. (Co-investigator), Porteous, D. (Co-investigator), Seckl, J. (Co-investigator), Starr, J. (Co-investigator), Wardlaw, J. (Co-investigator) & Okely, J. (Researcher)
1/09/13 → 31/08/19
Project: Research
Disconnected Mind [Phase 2]
Wardlaw, J. (Principal Investigator)
UK-based charities
1/01/11 → 31/03/16
Project: Research

Cite this

LifeLines Cohort Study, 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., ... Dunlop, M. G. (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{8f460de0ca684b089d58f75e12999c18,

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.",

author = "{LifeLines Cohort Study} and 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 Wild, {Sarah H} and Albert Tenesa and Pau Navarro and Nicholas Hastie and Gail Davies and Gow, {Alan J} and Wilson, {James F} and Farrington, {Susan M} and Evropi Theodoratou and Ozren Polasek and Harry Campbell and Igor Rudan and Deary, {Ian J} and Wright, {Alan F} and Dunlop, {Malcolm G}",

note = "The whole genome association study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) (Ref. BB/F019394/1). The LBC1936 data collection was funded by Research Into Ageing (Ref. 251). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (Ref. G0700704/84698). Funding from the BBSRC, Engineering and Physical Sciences Research Council (EPSRC), Economic and Social Research Council (ESRC) and Medical Research Council (MRC) is gratefully acknowledged. ",

year = "2013",

month = feb,

doi = "10.1038/ng.2500",

language = "English",

volume = "45",

pages = "145--154",

journal = "Nature Genetics",

publisher = "Nature Research",

number = "2",

}

LifeLines Cohort Study, 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, Wild, SH , Tenesa, A , Navarro, P, Hastie, N, Davies, G, Gow, AJ, Wilson, JF , Farrington, SM , Theodoratou, E, Polasek, O, Campbell, H , Rudan, I , Deary, IJ, Wright, AF & Dunlop, MG 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 - LifeLines Cohort Study

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 - Wild, Sarah H

AU - Tenesa, Albert

AU - Navarro, Pau

AU - Hastie, Nicholas

AU - Davies, Gail

AU - Gow, Alan J

AU - Wilson, James F

AU - Farrington, Susan M

AU - Theodoratou, Evropi

AU - Polasek, Ozren

AU - Campbell, Harry

AU - Rudan, Igor

AU - Deary, Ian J

AU - Wright, Alan F

AU - Dunlop, Malcolm G

N1 - The whole genome association study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) (Ref. BB/F019394/1). The LBC1936 data collection was funded by Research Into Ageing (Ref. 251). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (Ref. G0700704/84698). Funding from the BBSRC, Engineering and Physical Sciences Research Council (EPSRC), Economic and Social Research Council (ESRC) and Medical Research Council (MRC) is gratefully acknowledged.

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.

U2 - 10.1038/ng.2500

DO - 10.1038/ng.2500

M3 - Article

C2 - 23263486

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

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Projects

Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

Disconnected Mind [Phase 2]

Cite this