A genome-wide association analysis reveals new pathogenic pathways in gout*
Major, Tanya J.; Takei, Riku; Matsuo, Hirotaka; Leask, Megan P.; Sumpter, Nicholas A.; Topless, Ruth K.; Shirai, Yuya; Wang, Wei; Cadzow, Murray J.; Phipps-Green, Amanda J.; Li, Zhiqiang; Ji, Aichang; Merriman, Marilyn E.; Morice, Emily; Kelley, Eric E.; Wei, Wen Hua; McCormick, Sally P.A.; Bixley, Matthew J.; Reynolds, Richard J.; Saag, Kenneth G.; Fadason, Tayaza; Golovina, Evgenia; O’Sullivan, Justin M.; Stamp, Lisa K.; Dalbeth, Nicola; Abhishek, Abhishek; Doherty, Michael; Roddy, Edward; Jacobsson, Lennart T.H.; Kapetanovic, Meliha C.; Melander, Olle; Andrés, Mariano; Pérez-Ruiz, Fernando; Torres, Rosa J.; Radstake, Timothy; Jansen, Timothy L.; Janssen, Matthijs; Joosten, Leo A.B.; Liu, Ruiqi; Gaal, Orsolya I.; Crişan, Tania O.; Rednic, Simona; Kurreeman, Fina; Huizinga, Tom W.J.; Toes, René; Lioté, Frédéric; Richette, Pascal; Bardin, Thomas; Ea, Hang Korng; Pascart, Tristan; FAST Study Group; Japan Gout Genomics Consortium; Asia Pacific Gout Consortium; GlobalGout Genetics Consortium; 23andMe Research Team
(2024) Nature genetics, volume 56, issue 11, pp. 2392 - 2406
(Article)
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
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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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Keywords: Genetics
ISSN: 1061-4036
Publisher: Nature Research
Note: Publisher Copyright: © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024. corrected publication 2024.
(Peer reviewed)