A genome-wide association analysis reveals new pathogenic pathways in gout*

Tanya J. Major; Riku Takei; Hirotaka Matsuo; Megan P. Leask; Nicholas A. Sumpter; Ruth K. Topless; Yuya Shirai; Wei Wang; Murray J. Cadzow; Amanda J. Phipps-Green; Zhiqiang Li; Aichang Ji; Marilyn E. Merriman; Emily Morice; Eric E. Kelley; Wen Hua Wei; Sally P.A. McCormick; Matthew J. Bixley; Richard J. Reynolds; Kenneth G. Saag; Tayaza Fadason; Evgenia Golovina; Justin M. O’Sullivan; Lisa K. Stamp; Nicola Dalbeth; Abhishek Abhishek; Michael Doherty; Edward Roddy; Lennart T.H. Jacobsson; Meliha C. Kapetanovic; Olle Melander; Mariano Andrés; Fernando Pérez-Ruiz; Rosa J. Torres; Timothy Radstake; Timothy L. Jansen; Matthijs Janssen; Leo A.B. Joosten; Ruiqi Liu; Orsolya I. Gaal; Tania O. Crişan; Simona Rednic; Fina Kurreeman; Tom W.J. Huizinga; René Toes; Frédéric Lioté; Pascal Richette; Thomas Bardin; Hang Korng Ea; Tristan Pascart

doi:10.1038/s41588-024-01921-5

A genome-wide association analysis reveals new pathogenic pathways in gout*

Tanya J. Major, Riku Takei, Hirotaka Matsuo, Megan P. Leask, Nicholas A. Sumpter, Ruth K. Topless, Yuya Shirai, Wei Wang, Murray J. Cadzow, Amanda J. Phipps-Green, Zhiqiang Li, Aichang Ji, Marilyn E. Merriman, Emily Morice, Eric E. Kelley, Wen Hua Wei, Sally P.A. McCormick, Matthew J. Bixley, Richard J. Reynolds, Kenneth G. SaagTayaza Fadason, Evgenia Golovina, Justin M. O’Sullivan, Lisa K. Stamp, Nicola Dalbeth, Abhishek Abhishek, Michael Doherty, Edward Roddy, Lennart T.H. Jacobsson, Meliha C. Kapetanovic, Olle Melander, Mariano Andrés, Fernando Pérez-Ruiz, Rosa J. Torres, Timothy Radstake, Timothy L. Jansen, Matthijs Janssen, Leo A.B. Joosten, Ruiqi Liu, Orsolya I. Gaal, Tania O. Crişan, Simona Rednic, Fina Kurreeman, Tom W.J. Huizinga, René Toes, Frédéric Lioté, Pascal Richette, Thomas Bardin, Hang Korng Ea, Tristan Pascart, , , , ,

Rheumatology & Clinical Immunology

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

Abstract

Gout is a chronic disease that is caused by an innate immune response to deposited monosodium urate crystals in the setting of hyperuricemia. Here, we provide insights into the molecular mechanism of the poorly understood inflammatory component of gout from a genome-wide association study (GWAS) of 2.6 million people, including 120,295 people with prevalent gout. We detected 377 loci and 410 genetically independent signals (149 previously unreported loci in urate and gout). An additional 65 loci with signals in urate (from a GWAS of 630,117 individuals) but not gout were identified. A prioritization scheme identified candidate genes in the inflammatory process of gout, including genes involved in epigenetic remodeling, cell osmolarity and regulation of NOD-like receptor protein 3 (NLRP3) inflammasome activity. Mendelian randomization analysis provided evidence for a causal role of clonal hematopoiesis of indeterminate potential in gout. Our study identifies candidate genes and molecular processes in the inflammatory pathogenesis of gout suitable for follow-up studies.

Original language	English
Pages (from-to)	2392-2406
Number of pages	15
Journal	Nature genetics
Volume	56
Issue number	11
Early online date	15 Oct 2024
DOIs	https://doi.org/10.1038/s41588-024-01921-5
Publication status	Published - Nov 2024

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10.1038/s41588-024-01921-5

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Major, T. J., Takei, R., Matsuo, H., Leask, M. P., Sumpter, N. A., Topless, R. K., Shirai, Y., Wang, W., Cadzow, M. J., Phipps-Green, A. J., Li, Z., Ji, A., Merriman, M. E., Morice, E., Kelley, E. E., Wei, W. H., McCormick, S. P. A., Bixley, M. J., Reynolds, R. J. (2024). A genome-wide association analysis reveals new pathogenic pathways in gout*. Nature genetics, 56(11), 2392-2406. https://doi.org/10.1038/s41588-024-01921-5

@article{470c4b8b3e3446d083d198ae81d875b6,

title = "A genome-wide association analysis reveals new pathogenic pathways in gout*",

abstract = "Gout is a chronic disease that is caused by an innate immune response to deposited monosodium urate crystals in the setting of hyperuricemia. Here, we provide insights into the molecular mechanism of the poorly understood inflammatory component of gout from a genome-wide association study (GWAS) of 2.6 million people, including 120,295 people with prevalent gout. We detected 377 loci and 410 genetically independent signals (149 previously unreported loci in urate and gout). An additional 65 loci with signals in urate (from a GWAS of 630,117 individuals) but not gout were identified. A prioritization scheme identified candidate genes in the inflammatory process of gout, including genes involved in epigenetic remodeling, cell osmolarity and regulation of NOD-like receptor protein 3 (NLRP3) inflammasome activity. Mendelian randomization analysis provided evidence for a causal role of clonal hematopoiesis of indeterminate potential in gout. Our study identifies candidate genes and molecular processes in the inflammatory pathogenesis of gout suitable for follow-up studies.",

author = "Major, {Tanya J.} and Riku Takei and Hirotaka Matsuo and Leask, {Megan P.} and Sumpter, {Nicholas A.} and Topless, {Ruth K.} and Yuya Shirai and Wei Wang and Cadzow, {Murray J.} and Phipps-Green, {Amanda J.} and Zhiqiang Li and Aichang Ji and Merriman, {Marilyn E.} and Emily Morice and Kelley, {Eric E.} and Wei, {Wen Hua} and McCormick, {Sally P.A.} and Bixley, {Matthew J.} and Reynolds, {Richard J.} and Saag, {Kenneth G.} and Tayaza Fadason and Evgenia Golovina and O{\textquoteright}Sullivan, {Justin M.} and Stamp, {Lisa K.} and Nicola Dalbeth and Abhishek Abhishek and Michael Doherty and Edward Roddy and Jacobsson, {Lennart T.H.} and Kapetanovic, {Meliha C.} and Olle Melander and Mariano Andr{\'e}s and Fernando P{\'e}rez-Ruiz and Torres, {Rosa J.} and Timothy Radstake and Jansen, {Timothy L.} and Matthijs Janssen and Joosten, {Leo A.B.} and Ruiqi Liu and Gaal, {Orsolya I.} and Cri{\c s}an, {Tania O.} and Simona Rednic and Fina Kurreeman and Huizinga, {Tom W.J.} and Ren{\'e} Toes and Fr{\'e}d{\'e}ric Liot{\'e} and Pascal Richette and Thomas Bardin and Ea, {Hang Korng} and Tristan Pascart",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2024. corrected publication 2024.",

year = "2024",

month = nov,

doi = "10.1038/s41588-024-01921-5",

language = "English",

volume = "56",

pages = "2392--2406",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "11",

}

Major, TJ, Takei, R, Matsuo, H, Leask, MP, Sumpter, NA, Topless, RK, Shirai, Y, Wang, W, Cadzow, MJ, Phipps-Green, AJ, Li, Z, Ji, A, Merriman, ME, Morice, E, Kelley, EE, Wei, WH, McCormick, SPA, Bixley, MJ, Reynolds, RJ, Saag, KG, Fadason, T, Golovina, E, O’Sullivan, JM, Stamp, LK, Dalbeth, N, Abhishek, A, Doherty, M, Roddy, E, Jacobsson, LTH, Kapetanovic, MC, Melander, O, Andrés, M, Pérez-Ruiz, F, Torres, RJ, Radstake, T, Jansen, TL, Janssen, M, Joosten, LAB, Liu, R, Gaal, OI, Crişan, TO, Rednic, S, Kurreeman, F, Huizinga, TWJ, Toes, R, Lioté, F, Richette, P, Bardin, T, Ea, HK, Pascart, T 2024, 'A genome-wide association analysis reveals new pathogenic pathways in gout*', Nature genetics, vol. 56, no. 11, pp. 2392-2406. https://doi.org/10.1038/s41588-024-01921-5

TY - JOUR

T1 - A genome-wide association analysis reveals new pathogenic pathways in gout*

AU - Major, Tanya J.

AU - Takei, Riku

AU - Matsuo, Hirotaka

AU - Leask, Megan P.

AU - Sumpter, Nicholas A.

AU - Topless, Ruth K.

AU - Shirai, Yuya

AU - Wang, Wei

AU - Cadzow, Murray J.

AU - Phipps-Green, Amanda J.

AU - Li, Zhiqiang

AU - Ji, Aichang

AU - Merriman, Marilyn E.

AU - Morice, Emily

AU - Kelley, Eric E.

AU - Wei, Wen Hua

AU - McCormick, Sally P.A.

AU - Bixley, Matthew J.

AU - Reynolds, Richard J.

AU - Saag, Kenneth G.

AU - Fadason, Tayaza

AU - Golovina, Evgenia

AU - O’Sullivan, Justin M.

AU - Stamp, Lisa K.

AU - Dalbeth, Nicola

AU - Abhishek, Abhishek

AU - Doherty, Michael

AU - Roddy, Edward

AU - Jacobsson, Lennart T.H.

AU - Kapetanovic, Meliha C.

AU - Melander, Olle

AU - Andrés, Mariano

AU - Pérez-Ruiz, Fernando

AU - Torres, Rosa J.

AU - Radstake, Timothy

AU - Jansen, Timothy L.

AU - Janssen, Matthijs

AU - Joosten, Leo A.B.

AU - Liu, Ruiqi

AU - Gaal, Orsolya I.

AU - Crişan, Tania O.

AU - Rednic, Simona

AU - Kurreeman, Fina

AU - Huizinga, Tom W.J.

AU - Toes, René

AU - Lioté, Frédéric

AU - Richette, Pascal

AU - Bardin, Thomas

AU - Ea, Hang Korng

AU - Pascart, Tristan

N1 - Publisher Copyright: © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024. corrected publication 2024.

PY - 2024/11

Y1 - 2024/11

N2 - Gout is a chronic disease that is caused by an innate immune response to deposited monosodium urate crystals in the setting of hyperuricemia. Here, we provide insights into the molecular mechanism of the poorly understood inflammatory component of gout from a genome-wide association study (GWAS) of 2.6 million people, including 120,295 people with prevalent gout. We detected 377 loci and 410 genetically independent signals (149 previously unreported loci in urate and gout). An additional 65 loci with signals in urate (from a GWAS of 630,117 individuals) but not gout were identified. A prioritization scheme identified candidate genes in the inflammatory process of gout, including genes involved in epigenetic remodeling, cell osmolarity and regulation of NOD-like receptor protein 3 (NLRP3) inflammasome activity. Mendelian randomization analysis provided evidence for a causal role of clonal hematopoiesis of indeterminate potential in gout. Our study identifies candidate genes and molecular processes in the inflammatory pathogenesis of gout suitable for follow-up studies.

AB - Gout is a chronic disease that is caused by an innate immune response to deposited monosodium urate crystals in the setting of hyperuricemia. Here, we provide insights into the molecular mechanism of the poorly understood inflammatory component of gout from a genome-wide association study (GWAS) of 2.6 million people, including 120,295 people with prevalent gout. We detected 377 loci and 410 genetically independent signals (149 previously unreported loci in urate and gout). An additional 65 loci with signals in urate (from a GWAS of 630,117 individuals) but not gout were identified. A prioritization scheme identified candidate genes in the inflammatory process of gout, including genes involved in epigenetic remodeling, cell osmolarity and regulation of NOD-like receptor protein 3 (NLRP3) inflammasome activity. Mendelian randomization analysis provided evidence for a causal role of clonal hematopoiesis of indeterminate potential in gout. Our study identifies candidate genes and molecular processes in the inflammatory pathogenesis of gout suitable for follow-up studies.

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U2 - 10.1038/s41588-024-01921-5

DO - 10.1038/s41588-024-01921-5

M3 - Article

C2 - 39406924

AN - SCOPUS:85206813683

SN - 1061-4036

VL - 56

SP - 2392

EP - 2406

JO - Nature genetics

JF - Nature genetics

IS - 11

ER -

A genome-wide association analysis reveals new pathogenic pathways in gout*

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Correction to: A genome-wide association analysis reveals new pathogenic pathways in gout (Nature Genetics, (2024), 10.1038/s41588-024-01921-5)

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