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.

Academic Rheumatology School of Medicine University of Nottingham Nottingham United Kingdom

Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University Qingdao University Qingdao China

Australian Parkinsons Mission Garvan Institute of Medical Research Sydney New South Wales Australia

Bio 10 Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders Collaborative Innovation Center for Brain Science Shanghai Jiao Tong University Shanghai China

Center for Biomedical Network Research on Rare Diseases ISCIII Madrid Spain

Center for Treatment of Rheumatic and Musculoskeletal Diseases Diakonhjemmet Hospital Oslo Norway

Centre for Genomic and Experimental Medicine Institute of Genetics and Cancer University of Edinburgh Edinburgh UK

Department of Biochemistry Hospital La Paz Institute for Health Research Madrid Spain

Department of Biochemistry University of Otago Dunedin New Zealand

Department of Bioengineering and Therapeutic Sciences and Institute for Human Genetics University of California San Francisco CA USA

Department of Bioinformatics and Life Science Soongsil University Seoul South Korea

Department of Biomedical Information Management National Defense Medical College Research Institute National Defense Medical College Saitama Japan

Department of Cancer Genome Research Sasaki Institute Sasaki Foundation Tokyo Japan

Department of Clinical Medicine Miguel Hernandez University Alicante Spain

Department of Clinical Sciences Lund Section of Rheumatology Lund University and Skåne University Hospital Lund Sweden

Department of Clinical Sciences Lund University Malmö Sweden

Department of Emergency and Internal Medicine Skåne University Hospital Malmö Sweden

Department of Genome Informatics Graduate School of Medicine The University of Tokyo Tokyo Japan

Department of Integrative Physiology and Bio Nano Medicine National Defense Medical College Saitama Japan

Department of Internal Medicine and Radboud Institute of Molecular Life Science Radboud University Medical Center Nijmegen The Netherlands

Department of Medical Biochemistry Kurume University School of Medicine Fukuoka Japan

Department of Medical Genetics Iuliu Hațieganu University of Medicine and Pharmacy Cluj Napoca Romania

Department of Medicine University of Auckland Auckland New Zealand

Department of Medicine University of Otago Christchurch Christchurch New Zealand

Department of Microbiology and Immunology University of Otago Dunedin New Zealand

Department of Pathophysiology Tokyo University of Pharmacy and Life Sciences Tokyo Japan

Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Pharmacy The University of Tokyo Hospital Tokyo Japan

Department of Physiology and Pharmacology West Virginia University Morgantown WV USA

Department of Rheumatology and Clinical Immunology University Medical Center Utrecht The Netherlands

Department of Rheumatology and Inflammation Research Sahlgrenska Academy University of Gothenburg Gothenburg Sweden

Department of Rheumatology Austin Hospital Melbourne Victoria Australia

Department of Rheumatology Hopital Saint Philibert Lille Catholic University Lille France

Department of Rheumatology Iuliu Hatieganu University of Medicine and Pharmacy Cluj Napoca Cluj Romania

Department of Rheumatology Leiden University Medical Center Leiden The Netherlands

Department of Rheumatology Mater Misericordiae University Hospital and School of Medicine University College Dublin Ireland

Department of Rheumatology University Clinic 'Carl Gustav Carus' at the Technical University Dresden Germany

Department of Rheumatology VieCuri Medical Centre Venlo The Netherlands

Department of Statistical Genetics Osaka University Graduate School of Medicine Osaka Japan

Department of Women's and Children's Health University of Otago Dunedin New Zealand

Discipline of Medicine University of Adelaide Adelaide Australia

Division of Cancer Epidemiology and Prevention Aichi Cancer Center Aichi Japan

Division of Cancer Epidemiology Nagoya University Graduate School of Medicine Aichi Japan

Division of Clinical Immunology and Rheumatology University of Alabama at Birmingham Birmingham AL USA

Division of Research Kaiser Permanente Northern California Oakland CA USA

Division of Rheumatology Allergy and Immunology Massachusetts General Hospital Harvard Medical School Boston MA USA

Division of Rheumatology Brigham and Women's Hospital Harvard Medical School Boston MA USA

Flinders University Adelaide South Australia Australia

Genomics R and D 23andMe Inc Sunnyvale CA USA

Haywood Academic Rheumatology Centre Midlands Partnership University NHS Foundation Trust Stoke on Trent UK

Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai New York NY USA

Institute of Health and Biomedical Innovation Translational Research Institute Queensland University of Technology Brisbane Australia

Institute of Rheumatology Prague Czech Republic

Laboratory for Systems Genetics RIKEN Center for Integrative Medical Sciences Yokohama Japan

Liggins Institute University of Auckland Auckland New Zealand

Medical Research Council Human Genetics Unit Institute of Genetics and Cancer University of Edinburgh Edinburgh United Kingdom

MEMO Research Division of Molecular and Clinical Medicine University of Dundee Medical School Ninewells Hospital Dundee United Kingdom

MRC Lifecourse Epidemiology Unit University of Southampton Southampton United Kingdom

Osakidetza OSI EE Cruces BIOBizkaia Health Research Institute and Medicine Department of Medicine and Nursery School University of the Basque Country Biskay Spain

Penn The Children's Hospital of Pennsylvania Kidney Innovation Center Perelman School of Medicine University of Pennsylvania Philadelphia PA 19101 USA

Public Health Informatics Unit Department of Integrated Health Sciences Nagoya University Graduate School of Medicine Aichi Japan

Renal Electrolyte and Hypertension Division Department of Medicine Perelman School of Medicine University of Pennsylvania Philadelphia PA 19101 USA

Rheumatology Department Dr Balmis General University Hospital ISABIAL Alicante Spain

Rheumatology Department Feel'Gout GH Paris Saint Joseph Paris France

Rheumatology Department INSERM U1132 BIOSCAR University Paris Cité Lariboisière Hospital Paris France

Rheumatology Department The Queen Elizabeth Hospital Woodville South South Australia Australia

School of Clinical Medicine Faculty of Medicine University of Queensland Brisbane Australia

School of Medicine Keele University Keele Staffordshire United Kingdom

Service of Rheumatology Center Hospitalier Universitaire Vaudois Lausanne Switzerland

Shandong Provincial Key Laboratory of Metabolic Diseases Shandong Provincial Clinical Research Center for Immune Diseases and Gout the Affiliated Hospital of Qingdao University Qingdao Shandong China

Singapore Institute for Clinical Sciences Agency for Science Technology and Research Singapore Singapore

The Biomedical Sciences Institute and The Affiliated Hospital of Qingdao University Qingdao University Qingdao Shandong China

The Institute of Metabolic Diseases Qingdao University Qingdao Shandong China

The Japan Multi Institutional Collaborative Cohort Study Tokyo Japan

University of Lausanne Lausanne Switzerland

Viscient Biosciences 5752 Oberlin Dr Suite 111 San Diego CA 92121 USA

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Nat Genet. 2024 Nov;56(11):2577. doi: 10.1038/s41588-024-02017-w. PubMed

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Identification of pathogenic variants in the ABCG2 gene in patients with severe familial hyperuricemia and gout