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 at XDH, encoding the urate-producing enzyme xanthine oxidoreductase (XOR), co-localizes with genetic control of XDH expression, 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.

The authors have declared no competing interest.

This study was supported by grants from the New Zealand Health Research of New Zealand (08/075, 11/1075, 14/527), Arthritis New Zealand, Lottery Health New Zealand, JSPS KAKENHI Grant Numbers (20H00566, 21KK0173, 17H04128, 22H00476, 20K23152, 21H03350, 221S0002, 16H06279 [PAGS], 16H06277 [CoBiA], 20H00568), AMED (JP21gm4010006, JP22km0405211, JP22ek0410075, JP22km0405217, JP22ek0109594), JST Moonshot R&D (JPMJMS2021, JPMJMS2024), Takeda Science Foundation, Bioinformatics Initiative of Osaka University Graduate School of Medicine, the Gout and Uric Acid Foundation of Japan and the Ministry of Defense of Japan, the National Natural Science Foundation of China (82220108015) and National Key Research and Development Program of China (2022YFE0107600; 2022YFC2503300). Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006] and is currently supported by the Wellcome Trust [216767/Z/19/Z]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK, the Wellcome Trust (Wellcome Trust Strategic Award 'STratifying Resilience and Depression Longitudinally' (STRADL) Reference 104036/Z/14/Z) and by MRC University Unit grant MC_UU_00007/10 (QTL in Health and Disease programme).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

23andme: Participants provided informed consent and participated in the research online, under a protocol approved by the external AAHRPP accredited IRB, Ethical and Independent Review Services (www.eandireview.com). UK Biobank: The UK Biobank (UKBB) was undertaken with ethical approval from the North West Multi-Centre Research Ethics Committee of the UK. GlobalGout: The New Zealand Multiregional Ethics Committee (MEC05/10/130); The Northern Y Region Health Research Ethics Committee (Ngati Porou Hauora Charitable Trust study; NTY07/07/074); Research and Ethics Committee, Repatriation General Hospital, South Australia (32/08); Research Ethics Committee, University of New South Wales; Ethikkommission, Technische Universitat Dresden (EK 8012012); South East Scotland Research Ethics Committee (04/S1102/41); Commission Cantonale (VD) D'ethique de la Recherche sur l'etre Humain, Universite de Lausanne; Commissie Mensgebonden Onderzoek regio Arnhem/Nijmegen; Partners Health Care System Institutional Review Board. Kaiser Permanente: The Institutional Review Board of the Kaiser Foundation Research Institute. FinnGen: Coordinating Ethical Committee of the Hospital District of Helsinki and Uusimaa. China: Ethics review board at the Affiliated Hospital of Qingdao University. Japan: Institutional ethical committees of National Defense Medical College, Nagoya University and RIKEN. FAST: UK MultiCentre Research Ethics Committee (Reference number: 2011/001883/23) and the Medicines and Healthcare Products Regulatory Agency (Reference number: 11/AL/0311); NHS Tayside Committee on Medical Research Ethics (REC Reference Number: 05/S1401/89).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors