Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels

Adrienne Tin; Jonathan Marten; Victoria L Halperin Kuhns; Yong Li; Matthias Wuttke; Holger Kirsten; Karsten B Sieber; Chengxiang Qiu; Mathias Gorski; Zhi Yu; Ayush Giri; Gardar Sveinbjornsson; Man Li; Audrey Y Chu; Anselm Hoppmann; Luke J O'Connor; Bram Prins; Teresa Nutile; Damia Noce; Masato Akiyama; Massimiliano Cocca; Sahar Ghasemi; Peter J van der Most; Katrin Horn; Yizhe Xu; Christian Fuchsberger; Sanaz Sedaghat; Saima Afaq; Najaf Amin; Johan Ärnlöv; Stephan J L Bakker; Nisha Bansal; Daniela Baptista; Sven Bergmann; Mary L Biggs; Ginevra Biino; Eric Boerwinkle; Erwin P Bottinger; Thibaud S Boutin; Marco Brumat; Ralph Burkhardt; Eric Campana; Archie Campbell; Harry Campbell; Robert J Carroll; Eulalia Catamo; John C Chambers; Marina Ciullo; Maria Pina Concas; Josef Coresh; Tanguy Corre; Daniele Cusi; Sala Cinzia Felicita; Martin H de Borst; Alessandro De Grandi; Renée de Mutsert; Aiko P J de Vries; Graciela Delgado; Ayşe Demirkan; Olivier Devuyst; Katalin Dittrich; Kai-Uwe Eckardt; Georg Ehret; Karlhans Endlich; Michele K Evans; Ron T Gansevoort; Paolo Gasparini; Vilmantas Giedraitis; Christian Gieger; Giorgia Girotto; Martin Gögele; Scott D Gordon; Daniel F Gudbjartsson; Vilmundur Gudnason; Toomas Haller; Pavel Hamet; Tamara B Harris; Caroline Hayward; Andrew A Hicks; Edith Hofer; Hilma Holm; Wei Huang; Nina Hutri-Kähönen; Shih-Jen Hwang; M Arfan Ikram; Raychel M Lewis; Erik Ingelsson; Johanna Jakobsdottir; Ingileif Jonsdottir; Helgi Jonsson; Peter K Joshi; Navya Shilpa Josyula; Bettina Jung; Mika Kähönen; Yoichiro Kamatani; Masahiro Kanai; Shona M Kerr; Wieland Kiess; Marcus E Kleber; Wolfgang Koenig; V. A. Million Veteran Program

doi:10.1038/s41588-019-0504-x

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Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels

Journal article

Peer reviewed

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels

Adrienne Tin, Jonathan Marten, Victoria L Halperin Kuhns, Yong Li, Matthias Wuttke, Holger Kirsten, Karsten B Sieber, Chengxiang Qiu, Mathias Gorski, Zhi Yu, …

Nature genetics, Vol.51(10), pp.1459-1474

01/10/2019

DOI: https://doi.org/10.1038/s41588-019-0504-x

PMID: 31578528

Abstract

ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics

Cardiovascular Diseases - blood

Cardiovascular Diseases - epidemiology

Cardiovascular Diseases - genetics

Cohort Studies

Genetic Loci

Genetic Markers

Genetic Predisposition to Disease

Genome-Wide Association Study

Gout - blood

Gout - epidemiology

Gout - genetics

Hepatocyte Nuclear Factor 1-alpha - genetics

Hepatocyte Nuclear Factor 4 - genetics

Humans

Kidney - metabolism

Kidney - pathology

Liver - metabolism

Liver - pathology

Metabolic Diseases - blood

Metabolic Diseases - epidemiology

Metabolic Diseases - genetics

Neoplasm Proteins - genetics

Organ Specificity

Polymorphism, Single Nucleotide

Signal Transduction

Uric Acid - blood

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

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Title: Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels
Creators: Adrienne Tin - Johns Hopkins University
Jonathan Marten - MRC Institute of Genetics and Molecular Medicine
Victoria L Halperin Kuhns - Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
Yong Li - University of Freiburg
Matthias Wuttke - University of Freiburg
Holger Kirsten - Leipzig University
Karsten B Sieber - Target
Chengxiang Qiu - University of Pennsylvania
Mathias Gorski - University Hospital Regensburg
Zhi Yu - Johns Hopkins University
Ayush Giri - Vanderbilt University Medical Center
Gardar Sveinbjornsson - deCODE Genetics
Man Li - University of Utah
Audrey Y Chu - MSD
Anselm Hoppmann - University of Freiburg
Luke J O'Connor - Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
Bram Prins - University of Cambridge
Teresa Nutile - Institute of Genetics and Biophysics
Damia Noce - Eurac Research
Masato Akiyama - RIKEN Center for Integrative Medical Sciences
Massimiliano Cocca - IRCCS Materno Infantile Burlo Garofolo
Sahar Ghasemi - Universitätsmedizin Greifswald
Peter J van der Most - University Medical Center Groningen
Katrin Horn - LIFE Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany
Yizhe Xu - University of Utah
Christian Fuchsberger - Eurac Research
Sanaz Sedaghat - Erasmus MC
Saima Afaq - Imperial College London
Najaf Amin - Erasmus MC
Johan Ärnlöv - Karolinska Institutet
Stephan J L Bakker - University Medical Center Groningen
Nisha Bansal - University of Washington
Daniela Baptista - University Hospital of Geneva
Sven Bergmann - University of Lausanne
Mary L Biggs - University of Washington
Ginevra Biino - National Research Council
Eric Boerwinkle - The University of Texas Health Science Center at Houston
Erwin P Bottinger - Icahn School of Medicine at Mount Sinai
Thibaud S Boutin - MRC Institute of Genetics and Molecular Medicine
Marco Brumat - University of Trieste
Ralph Burkhardt - University Hospital Regensburg
Eric Campana - University of Trieste
Archie Campbell - University of Edinburgh
Harry Campbell - University of Edinburgh
Robert J Carroll - Vanderbilt University Medical Center
Eulalia Catamo - IRCCS Materno Infantile Burlo Garofolo
John C Chambers - Imperial College London
Marina Ciullo - Institute of Genetics and Biophysics
Maria Pina Concas - IRCCS Materno Infantile Burlo Garofolo
Josef Coresh - Johns Hopkins University
Tanguy Corre - University of Lausanne
Daniele Cusi - National Research Council
Sala Cinzia Felicita - San Raffaele Research Institute, Milano, Italy
Martin H de Borst - University Medical Center Groningen
Alessandro De Grandi - Institute for Biomedicine
Renée de Mutsert - Leiden University Medical Center
Aiko P J de Vries - Leiden University
Graciela Delgado - University Medical Centre Mannheim
Ayşe Demirkan - Erasmus MC
Olivier Devuyst - University of Zurich
Katalin Dittrich - Centre for Pediatric Research, University of Leipzig, Leipzig, Germany
Kai-Uwe Eckardt - Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
Georg Ehret - University Hospital of Geneva
Karlhans Endlich - German Centre for Cardiovascular Research
Michele K Evans - National Institutes of Health
Ron T Gansevoort - University Medical Center Groningen
Paolo Gasparini - IRCCS Materno Infantile Burlo Garofolo
Vilmantas Giedraitis - Uppsala University
Christian Gieger - Helmholtz Zentrum München
Giorgia Girotto - IRCCS Materno Infantile Burlo Garofolo
Martin Gögele - Institute for Biomedicine
Scott D Gordon - QIMR Berghofer Medical Research Institute
Daniel F Gudbjartsson - deCODE Genetics
Vilmundur Gudnason - University of Iceland
Toomas Haller - University of Tartu
Pavel Hamet - Centre Hospitalier de l’Université de Montréal
Tamara B Harris - National Institute on Aging
Caroline Hayward - University of Edinburgh
Andrew A Hicks - Eurac Research
Edith Hofer - Medical University of Graz
Hilma Holm - deCODE Genetics
Wei Huang - Chinese National Human Genome Center
Nina Hutri-Kähönen - Tampere University
Shih-Jen Hwang - National Heart Lung and Blood Institute
M Arfan Ikram - Erasmus MC
Raychel M Lewis - University of Maryland, Baltimore
Erik Ingelsson - Stanford University
Johanna Jakobsdottir - Icelandic Heart Association
Ingileif Jonsdottir - deCODE Genetics
Helgi Jonsson - National University Hospital of Iceland
Peter K Joshi - University of Edinburgh
Navya Shilpa Josyula - Geisinger Research, Biomedical and Translational Informatics Institute, Rockville, MD, USA
Bettina Jung - University Hospital Regensburg
Mika Kähönen - Tampere University
Yoichiro Kamatani - RIKEN Center for Integrative Medical Sciences
Masahiro Kanai - RIKEN Center for Integrative Medical Sciences
Shona M Kerr - MRC Institute of Genetics and Molecular Medicine
Wieland Kiess - Centre for Pediatric Research, University of Leipzig, Leipzig, Germany
Marcus E Kleber - University Medical Centre Mannheim
Wolfgang Koenig - Deutsches Herzzentrum München
V. A. Million Veteran Program
Publication Details: Nature genetics, Vol.51(10), pp.1459-1474
Date published: 01/10/2019
Grant note: U01 HL130114 / NHLBI NIH HHS R01 HL120393 / NHLBI NIH HHS P30 DK116074 / NIDDK NIH HHS RG/13/13/30194 / British Heart Foundation U01 HL120393 / NHLBI NIH HHS R01 AR073178 / NIAMS NIH HHS R01 HL105756 / NHLBI NIH HHS RG/18/13/33946 / British Heart Foundation MC_QA137853 / Medical Research Council 212945/Z/18/Z / Wellcome Trust
Identifiers: 99928816402346
Academic Unit: Institute for Sustainability; Surrey Institute for People-Centred AI; School of Biosciences
Language: English
Resource Type: Journal article

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels

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