A genome-wide association analysis of 2,622,830 individuals reveals new pathogenic pathways in gout
Authors: Major Tanya J. , Takei Riku , Matsuo Hirotaka , Leask Megan P. , Topless Ruth K. , Shirai Yuya , Li Zhiqiang , Ji Aichang , Cadzow Murray J. , Sumpter Nicholas A. , Merriman Marilyn E. , Phipps-Green Amanda J. , Urquiaga Mariana , Kelley Eric E. , King Rachel D. , Lewis Sara E. , Maxwell Brooke A. , Wei Wen-Hua , McCormick Sally P.A. , Reynolds Richard J. , Saag Kenneth G. , Bixley Matthew J. , Fadason Tayaza , 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 Orsi , Crişan Tania O. , Rednic Simona , Kurreeman Fina , Huizinga Tom W.J. , Toes René , Lioté Frédéric , Richette Pascal , Bardin Thomas , Ea Hang Korng , Pascart Tristan , McCarthy Geraldine M. , Helbert Laura , Stibůrková Blanka , Tausche Anne-K. , Uhlig Till , Vitart Véronique , Boutin Thibaud S. , Hayward Caroline , Riches Philip L. , Ralston Stuart H. , Campbell Archie , MacDonald Thomas M. , Nakayama Akiyoshi , Takada Tappei , Nakatochi Masahiro , Shimizu Seiko , Kawamura Yusuke , Toyoda Yu , Nakaoka Hirofumi , Yamamoto Ken , Matsuo Keitaro , Shinomiya Nariyoshi , Ichida Kimiyoshi ,   Japan Gout Genomics Consortium, Lee Chaeyoung , Bradbury Linda A. , Brown Matthew A. , Robinson Philip C. , Buchanan Russell R.C. , Hill Catherine L. , Lester Susan , Smith Malcolm D. , Rischmueller Maureen , Choi Hyon K. , Stahl Eli A. , Miner Jeff N. , Solomon Daniel H. , Cui Jing , Giacomini Kathleen M. , Brackman Deanna J. , Jorgenson Eric M. ,   23andMe Research Team, Wang Wei , Shringarpure Suyash , So Alexander , Okada Yukinori , Li Changgui , Shi Yongyong , Merriman Tony R. 
Published: November 2022

Gout is a chronic disease of monosodium urate crystal deposition in the setting of hyperuricemia that typically presents with recurrent flares of acute inflammatory arthritis that occur due to innate immune response to deposited crystals. The molecular mechanism of the progression from hyperuricemia to clinical gout is poorly understood. Here we provide insights into this progression from a genetic study of 2.6 million people, including 120,282 people with gout. We detected 376 loci and 410 genetically independent signals (148 new loci in urate and gout). We identified 1,768 candidate genes with subsequent pathway analysis revealing urate metabolism, type 2 diabetes, and chromatin modification and structure as top pathways in gout. Genes located within or statistically linked to significant GWAS loci were prioitized for their potential to control the progression from hyperuricemia to gout. This identified strong candidate immune genes involved in epigenetic remodelling, cell osmolarity, and regulation of NLRP3-inflammasome activity. The genetic association signal atXDH, encoding the urate-producing enzyme xanthine oxidoreductase (XOR), co-localizes with genetic control ofXDHexpression, but only in the prostate. We demonstrate XOR activity and urate production in the mouse prostate, and use single-cell RNA sequence data to propose a model of urate reuptake, synthesis, and secretion by the prostate. The gout-associated loci were over-represented for genes implicated in clonal hematopoeiesis of indeterminate potential (CHIP) and Mendelian randomization analysis provided evidence for a causal role of CHIP in gout. In concert with implication of epigenomic regulators, this provides support for epigenomic remodelling as causal in gout. We provide new insights into the molecular pathogenesis of gout and identify an array of candidate genes for a role in the inflammatory process of gout.