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

Tanya J Major; Riku Takei; Hirotaka Matsuo; Megan P Leask; Nicholas A Sumpter; Ruth K Topless; Yuya Shirai; Wei Wang; Murray J Cadzow; Amanda J 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 Andrés; Fernando Pérez-Ruiz; Rosa J Torres; Timothy Radstake; Timothy L Jansen; Matthijs Janssen; Leo A B Joosten; Ruiqi Liu; Orsolya I Gaal; Tania O Crişan; Simona Rednic; Fina Kurreeman; Tom W J Huizinga; René Toes; Frédéric Lioté; Pascal Richette; Thomas Bardin; Hang Korng Ea; Tristan Pascart; Geraldine M McCarthy; Laura Helbert; Blanka Stibůrková; Anne-K Tausche; Till Uhlig; Véronique Vitart; Thibaud S Boutin; Caroline Hayward; Philip L Riches; Stuart H Ralston; Archie Campbell; Thomas M MacDonald; FAST Study Group; Akiyoshi Nakayama; Tappei Takada; Masahiro Nakatochi; Seiko Shimizu; Yusuke Kawamura; Yu Toyoda; Hirofumi Nakaoka; Ken Yamamoto; Keitaro Matsuo; Nariyoshi Shinomiya; Kimiyoshi Ichida; Japan Gout Genomics Consortium; Chaeyoung Lee; Asia Pacific Gout Consortium; 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; GlobalGout Genetics Consortium; Hongbo Liu; Katalin Susztak; 23andMe Research Team; 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

Nat Genet. 2024 Oct 15. doi: 10.1038/s41588-024-01921-5. Online ahead of print.

Authors

Tanya J Major^#¹, Riku Takei^#², Hirotaka Matsuo^#^{3

4}, Megan P Leask^#², Nicholas A Sumpter^#², Ruth K Topless^#¹, Yuya Shirai^#⁵, Wei Wang^#⁶, Murray J Cadzow¹, Amanda J Phipps-Green¹, Zhiqiang Li⁷, Aichang Ji^{8

9}, Marilyn E Merriman², Emily Morice², Eric E Kelley¹⁰, Wen-Hua Wei^{1

11}, Sally P A McCormick¹, Matthew J Bixley¹, Richard J Reynolds², Kenneth G Saag², Tayaza Fadason¹², Evgenia Golovina¹², Justin M O'Sullivan^{12

13

14

15}, Lisa K Stamp¹⁶, Nicola Dalbeth¹⁷, Abhishek Abhishek¹⁸, Michael Doherty¹⁸, Edward Roddy^{19

20}, Lennart T H Jacobsson²¹, Meliha C Kapetanovic²², Olle Melander^{23

24}, Mariano Andrés^{25

26}, Fernando Pérez-Ruiz²⁷, Rosa J Torres^{28

29}, Timothy Radstake³⁰, Timothy L Jansen³¹, Matthijs Janssen³¹, Leo A B Joosten^{32

33}, Ruiqi Liu³², Orsolya I Gaal³³, Tania O Crişan³³, Simona Rednic³⁴, Fina Kurreeman³⁵, Tom W J Huizinga³⁵, René Toes³⁵, Frédéric Lioté^{36

37}, Pascal Richette³⁷, Thomas Bardin³⁷, Hang Korng Ea³⁷, Tristan Pascart³⁸, Geraldine M McCarthy³⁹, Laura Helbert³⁹, Blanka Stibůrková^{40

41}, Anne-K Tausche⁴², Till Uhlig⁴³, Véronique Vitart⁴⁴, Thibaud S Boutin⁴⁴, Caroline Hayward⁴⁴, Philip L Riches⁴⁵, Stuart H Ralston⁴⁵, Archie Campbell⁴⁵, Thomas M MacDonald⁴⁶; FAST Study Group; Akiyoshi Nakayama³, Tappei Takada⁴⁷, Masahiro Nakatochi⁴⁸, Seiko Shimizu³, Yusuke Kawamura^{2

3

49}, Yu Toyoda³, Hirofumi Nakaoka⁴⁹, Ken Yamamoto⁵⁰, Keitaro Matsuo^{51

52

53}, Nariyoshi Shinomiya³, Kimiyoshi Ichida⁵⁴; Japan Gout Genomics Consortium; Chaeyoung Lee⁵⁵; Asia Pacific Gout Consortium; Linda A Bradbury⁵⁶, Matthew A Brown⁵⁶, Philip C Robinson⁵⁷, Russell R C Buchanan⁵⁸, Catherine L Hill^{59

60}, Susan Lester^{59

60}, Malcolm D Smith⁶¹, Maureen Rischmueller^{59

60}, Hyon K Choi⁶², Eli A Stahl⁶³, Jeff N Miner⁶⁴, Daniel H Solomon⁶⁵, Jing Cui⁶⁵, Kathleen M Giacomini⁶⁶, Deanna J Brackman⁶⁶, Eric M Jorgenson⁶⁷; GlobalGout Genetics Consortium; Hongbo Liu^{68

69}, Katalin Susztak^{68

69}; 23andMe Research Team; Suyash Shringarpure⁶, Alexander So^{70

71}, Yukinori Okada^#^{5

72

73}, Changgui Li^#^{8

9}, Yongyong Shi^#^{74

75}, Tony R Merriman^{76

77

78}

Collaborator

Suyash Shringapure

Affiliations

¹ Department of Biochemistry, University of Otago, Dunedin, New Zealand.
² Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA.
³ Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Saitama, Japan.
⁴ Department of Biomedical Information Management, National Defense Medical College Research Institute, National Defense Medical College, Saitama, Japan.
⁵ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.
⁶ Genomics R&D, 23andMe, Inc, Sunnyvale, CA, USA.
⁷ The Biomedical Sciences Institute and The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, Shandong, China.
⁸ 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.
⁹ The Institute of Metabolic Diseases, Qingdao University, Qingdao, Shandong, China.
¹⁰ Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV, USA.
¹¹ Department of Women's and Children's Health, University of Otago, Dunedin, New Zealand.
¹² Liggins Institute, University of Auckland, Auckland, New Zealand.
¹³ MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom.
¹⁴ Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore, Singapore.
¹⁵ Australian Parkinsons Mission, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
¹⁶ Department of Medicine, University of Otago, Christchurch, Christchurch, New Zealand.
¹⁷ Department of Medicine, University of Auckland, Auckland, New Zealand.
¹⁸ Academic Rheumatology, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
¹⁹ School of Medicine, Keele University, Keele, Staffordshire, United Kingdom.
²⁰ Haywood Academic Rheumatology Centre, Midlands Partnership University NHS Foundation Trust, Stoke-on-Trent, UK.
²¹ Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
²² Department of Clinical Sciences Lund, Section of Rheumatology, Lund University and Skåne University Hospital, Lund, Sweden.
²³ Department of Clinical Sciences, Lund University, Malmö, Sweden.
²⁴ Department of Emergency and Internal Medicine, Skåne University Hospital, Malmö, Sweden.
²⁵ Rheumatology Department, Dr Balmis General University Hospital-ISABIAL, Alicante, Spain.
²⁶ Department of Clinical Medicine, Miguel Hernandez University, Alicante, Spain.
²⁷ Osakidetza, OSI-EE-Cruces, BIOBizkaia Health Research Institute and Medicine Department of Medicine and Nursery School, University of the Basque Country, Biskay, Spain.
²⁸ Department of Biochemistry, Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain.
²⁹ Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
³⁰ Department of Rheumatology and Clinical Immunology, University Medical Center, Utrecht, The Netherlands.
³¹ Department of Rheumatology, VieCuri Medical Centre, Venlo, The Netherlands.
³² Department of Internal Medicine and Radboud Institute of Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands.
³³ Department of Medical Genetics, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
³⁴ Department of Rheumatology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Cluj, Romania.
³⁵ Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
³⁶ Rheumatology Department, Feel'Gout, GH Paris Saint Joseph, Paris, France.
³⁷ Rheumatology Department, INSERM U1132, BIOSCAR, University Paris Cité, Lariboisière Hospital, Paris, France.
³⁸ Department of Rheumatology, Hopital Saint-Philibert, Lille Catholic University, Lille, France.
³⁹ Department of Rheumatology, Mater Misericordiae University Hospital and School of Medicine, University College, Dublin, Ireland.
⁴⁰ Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
⁴¹ Institute of Rheumatology, Prague, Czech Republic.
⁴² Department of Rheumatology, University Clinic 'Carl Gustav Carus' at the Technical University, Dresden, Germany.
⁴³ Center for Treatment of Rheumatic and Musculoskeletal Diseases, Diakonhjemmet Hospital, Oslo, Norway.
⁴⁴ Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom.
⁴⁵ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
⁴⁶ MEMO Research, Division of Molecular and Clinical Medicine, University of Dundee Medical School, Ninewells Hospital, Dundee, United Kingdom.
⁴⁷ Department of Pharmacy, The University of Tokyo Hospital, Tokyo, Japan.
⁴⁸ Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Aichi, Japan.
⁴⁹ Department of Cancer Genome Research, Sasaki Institute, Sasaki Foundation, Tokyo, Japan.
⁵⁰ Department of Medical Biochemistry, Kurume University School of Medicine, Fukuoka, Japan.
⁵¹ Division of Cancer Epidemiology & Prevention, Aichi Cancer Center, Aichi, Japan.
⁵² Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Aichi, Japan.
⁵³ The Japan Multi-Institutional Collaborative Cohort (J-MICC) Study, Tokyo, Japan.
⁵⁴ Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
⁵⁵ Department of Bioinformatics and Life Science, Soongsil University, Seoul, South Korea.
⁵⁶ Institute of Health and Biomedical Innovation, Translational Research Institute, Queensland University of Technology, Brisbane, Australia.
⁵⁷ School of Clinical Medicine, Faculty of Medicine, University of Queensland, Brisbane, Australia.
⁵⁸ Department of Rheumatology, Austin Hospital, Melbourne, Victoria, Australia.
⁵⁹ Rheumatology Department, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia.
⁶⁰ Discipline of Medicine, University of Adelaide, Adelaide, Australia.
⁶¹ Flinders University, Adelaide, South Australia, Australia.
⁶² Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁶³ Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶⁴ Viscient Biosciences, 5752 Oberlin Dr., Suite 111, San Diego, CA, 92121, USA.
⁶⁵ Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶⁶ Department of Bioengineering and Therapeutic Sciences and Institute for Human Genetics, University of California, San Francisco, CA, USA.
⁶⁷ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
⁶⁸ Penn / The Children's Hospital of Pennsylvania Kidney Innovation Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19101, USA.
⁶⁹ Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19101, USA.
⁷⁰ Service of Rheumatology, Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
⁷¹ University of Lausanne, Lausanne, Switzerland.
⁷² Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁷³ Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁷⁴ Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China.
⁷⁵ Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China.
⁷⁶ Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA. [email protected].
⁷⁷ The Institute of Metabolic Diseases, Qingdao University, Qingdao, Shandong, China. [email protected].
⁷⁸ Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand. [email protected].

^# Contributed equally.

PMID: 39406924
DOI: 10.1038/s41588-024-01921-5

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.