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

Tanya J. Major; Riku Takei; Hirotaka Matsuo; Megan Leask; Nicholas A. Sumpter; Ruth Topless; Yuya Shirai; Wei Wang; Murray Cadzow; Amanda 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 Andres; Fernando Perez-Ruiz; Rosa J. Torres; Timothy  Radstake; Timothy L Jansen; Matthijs Janssen; Leo A. B. Joosten; Ruiqi Liu; Orsolya I Gaal; Tania O Crisan; Simona Rednic; Fina Kurreeman; Tom W. J. Huizinga; Rene Toes; Frederic Lioté; P. Richette; Thomas Bardin; Hang Korng Ea; Tristan Pascart; Geraldine M McCarthy; Laura Helbert; Blanka Stiburkova; Anne-K Tausche; Till Uhlig; Veronique Vitart; Thibaud S Boutin; Caroline Hayward; Philip Riches; Stuart H Ralston; Archie Campbell; Thomas M Macdonald; Akiyoshi Nakayama; Tappei Takada; Masahiro Nakatochi; Seiko Shimizu; Yusuke Kawamura; Yu Toyoda; Hirofumi Nakaoka; Ken Yamamoto; Keitaro Matsuo; Nariyoshi Shinomiya; Kimiyoshi Ichida; Chaeyoung Lee; Linda A Bradbury; Matthew A. Brown; Philip C Robinson; Russell R C Buchanan; Catherine L Hill; Susan Lester; Malcolm D Smith; Maureen Rischmueller; Hyon K Choi; Eli A. Stahl; Jeff N Miner; Daniel H Solomon; Jing Cui; Kathleen M Giacomini; Deanna J Brackman; Eric M Jorgenson; Hongbo Liu; Katalin  Susztak; Suyash Shringarpure; Alexander So; Yukinori Okada; Changgui Li; Yongyong Shi; Tony R. Merriman

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 Leask, Nicholas A. Sumpter, Ruth Topless, Yuya Shirai, Wei Wang, Murray Cadzow, Amanda 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 Andres, Fernando Perez-Ruiz, Rosa J. Torres, Timothy Radstake, Timothy L Jansen, Matthijs Janssen, Leo A. B. Joosten, Ruiqi Liu, Orsolya I Gaal, Tania O Crisan, Simona Rednic, Fina Kurreeman, Tom W. J. Huizinga, Rene Toes, Frederic Lioté, P. Richette, Thomas Bardin, Hang Korng Ea, Tristan Pascart, Geraldine M McCarthy, Laura Helbert, Blanka Stiburkova, Anne-K Tausche, Till Uhlig, Veronique Vitart, Thibaud S Boutin, Caroline Hayward, Philip Riches, Stuart H Ralston, Archie Campbell, Thomas M Macdonald, Akiyoshi Nakayama, Tappei Takada, Masahiro Nakatochi, Seiko Shimizu, Yusuke Kawamura, Yu Toyoda, Hirofumi Nakaoka, Ken Yamamoto, Keitaro Matsuo, Nariyoshi Shinomiya, Kimiyoshi Ichida, Chaeyoung Lee, Linda A Bradbury, Matthew A. Brown, Philip C Robinson, Russell R C Buchanan, Catherine L Hill, Susan Lester, Malcolm D Smith, Maureen Rischmueller , Hyon K Choi, Eli A. Stahl, Jeff N Miner, Daniel H Solomon, Jing Cui, Kathleen M Giacomini, Deanna J Brackman, Eric M Jorgenson, Hongbo Liu, Katalin Susztak, Suyash Shringarpure, Alexander So, Yukinori Okada, Changgui Li, Yongyong Shi, Tony R. Merriman^*

^*Corresponding author for this work

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

Abstract / Description of output

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
Journal	Nature Genetics
Early online date	15 Oct 2024
DOIs	https://doi.org/10.1038/s41588-024-01921-5
Publication status	E-pub ahead of print - 15 Oct 2024

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10.1038/s41588-024-01921-5

NG-A61673R3_Merriman_-_EdVer_1723735318_1cleanAccepted author manuscript, 143 KBLicence: Creative Commons: Attribution (CC-BY)

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Major, T. J., Takei, R., Matsuo, H., Leask, M., Sumpter, N. A., Topless, R., Shirai, Y., Wang, W., Cadzow, M., Phipps-Green, A., 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., ... Merriman, T. R. (2024). A genome-wide association analysis reveals new pathogenic pathways in gout. Nature Genetics. Advance online publication. https://doi.org/10.1038/s41588-024-01921-5

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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 Megan Leask and Sumpter, {Nicholas A.} and Ruth Topless and Yuya Shirai and Wei Wang and Murray Cadzow and Amanda Phipps-Green and Zhiqiang Li and Aichang Ji and Merriman, {Marilyn E} and Emily Morice and Kelley, {Eric E} and Wen-Hua Wei 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'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 Andres and Fernando Perez-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 Crisan, {Tania O} and Simona Rednic and Fina Kurreeman and Huizinga, {Tom W. J.} and Rene Toes and Frederic Liot{\'e} and P. Richette and Thomas Bardin and Ea, {Hang Korng} and Tristan Pascart and McCarthy, {Geraldine M} and Laura Helbert and Blanka Stiburkova and Anne-K Tausche and Till Uhlig and Veronique Vitart and Boutin, {Thibaud S} and Caroline Hayward and Philip Riches and Ralston, {Stuart H} and Archie Campbell and Macdonald, {Thomas M} and Akiyoshi Nakayama and Tappei Takada and Masahiro Nakatochi and Seiko Shimizu and Yusuke Kawamura and Yu Toyoda and Hirofumi Nakaoka and Ken Yamamoto and Keitaro Matsuo and Nariyoshi Shinomiya and Kimiyoshi Ichida and Chaeyoung Lee and Bradbury, {Linda A} and Brown, {Matthew A.} and Robinson, {Philip C} and Buchanan, {Russell R C} and Hill, {Catherine L} and Susan Lester and Smith, {Malcolm D} and Maureen Rischmueller and Choi, {Hyon K} and Stahl, {Eli A.} and Miner, {Jeff N} and Solomon, {Daniel H} and Jing Cui and Giacomini, {Kathleen M} and Brackman, {Deanna J} and Jorgenson, {Eric M} and Hongbo Liu and Katalin Susztak and Suyash Shringarpure and Alexander So and Yukinori Okada and Changgui Li and Yongyong Shi and Merriman, {Tony R.}",

year = "2024",

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

language = "English",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

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Major, TJ, Takei, R, Matsuo, H, Leask, M, Sumpter, NA, Topless, R, Shirai, Y, Wang, W, Cadzow, M, Phipps-Green, A, Li, Z, Ji, A, Merriman, ME, Morice, E, Kelley, EE, Wei, W-H, 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, Andres, M, Perez-Ruiz, F, Torres, RJ, Radstake, T, Jansen, TL, Janssen, M, Joosten, LAB, Liu, R, Gaal, OI, Crisan, TO, Rednic, S, Kurreeman, F, Huizinga, TWJ, Toes, R, Lioté, F, Richette, P, Bardin, T, Ea, HK, Pascart, T, McCarthy, GM, Helbert, L, Stiburkova, B, Tausche, A-K, Uhlig, T, Vitart, V , Boutin, TS , Hayward, C , Riches, P , Ralston, SH , Campbell, A, Macdonald, TM, Nakayama, A, Takada, T, Nakatochi, M, Shimizu, S, Kawamura, Y, Toyoda, Y, Nakaoka, H, Yamamoto, K, Matsuo, K, Shinomiya, N, Ichida, K, Lee, C, Bradbury, LA, Brown, MA, Robinson, PC, Buchanan, RRC, Hill, CL, Lester, S, Smith, MD, Rischmueller , M, Choi, HK, Stahl, EA, Miner, JN, Solomon, DH, Cui, J, Giacomini, KM, Brackman, DJ, Jorgenson, EM, Liu, H, Susztak, K, Shringarpure, S, So, A, Okada, Y, Li, C, Shi, Y & Merriman, TR 2024, 'A genome-wide association analysis reveals new pathogenic pathways in gout', Nature Genetics. 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

AU - Sumpter, Nicholas A.

AU - Topless, Ruth

AU - Shirai, Yuya

AU - Wang, Wei

AU - Cadzow, Murray

AU - Phipps-Green, Amanda

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 - Andres, Mariano

AU - Perez-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 - Crisan, Tania O

AU - Rednic, Simona

AU - Kurreeman, Fina

AU - Huizinga, Tom W. J.

AU - Toes, Rene

AU - Lioté, Frederic

AU - Richette, P.

AU - Bardin, Thomas

AU - Ea, Hang Korng

AU - Pascart, Tristan

AU - McCarthy, Geraldine M

AU - Helbert, Laura

AU - Stiburkova, Blanka

AU - Tausche, Anne-K

AU - Uhlig, Till

AU - Vitart, Veronique

AU - Boutin, Thibaud S

AU - Hayward, Caroline

AU - Riches, Philip

AU - Ralston, Stuart H

AU - Campbell, Archie

AU - Macdonald, Thomas M

AU - Nakayama, Akiyoshi

AU - Takada, Tappei

AU - Nakatochi, Masahiro

AU - Shimizu, Seiko

AU - Kawamura, Yusuke

AU - Toyoda, Yu

AU - Nakaoka, Hirofumi

AU - Yamamoto, Ken

AU - Matsuo, Keitaro

AU - Shinomiya, Nariyoshi

AU - Ichida, Kimiyoshi

AU - Lee, Chaeyoung

AU - Bradbury, Linda A

AU - Brown, Matthew A.

AU - Robinson, Philip C

AU - Buchanan, Russell R C

AU - Hill, Catherine L

AU - Lester, Susan

AU - Smith, Malcolm D

AU - Rischmueller , Maureen

AU - Choi, Hyon K

AU - Stahl, Eli A.

AU - Miner, Jeff N

AU - Solomon, Daniel H

AU - Cui, Jing

AU - Giacomini, Kathleen M

AU - Brackman, Deanna J

AU - Jorgenson, Eric M

AU - Liu, Hongbo

AU - Susztak, Katalin

AU - Shringarpure, Suyash

AU - So, Alexander

AU - Okada, Yukinori

AU - Li, Changgui

AU - Shi, Yongyong

AU - Merriman, Tony R.

PY - 2024/10/15

Y1 - 2024/10/15

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.

U2 - 10.1038/s41588-024-01921-5

DO - 10.1038/s41588-024-01921-5

M3 - Article

SN - 1061-4036

JO - Nature Genetics

JF - Nature Genetics

ER -

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

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

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Generation Scotland: NextGenScot

Quantitative Traits in Health and Disease

Stratifying Resilience and Depression Longitudinally

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