Genome-wide association analyses identify 18 new loci associated with serum urate concentrations

  title={Genome-wide association analyses identify 18 new loci associated with serum urate concentrations},
  author={Anna K{\"o}ttgen and Eva Albrecht and Alexander Teumer and Veronique Vitart and Jan Krumsiek and Claudia Hundertmark and Giorgio Pistis and Daniela Ruggiero and Conall M. O’Seaghdha and Toomas Haller and Qiong Yang and Toshiko Tanaka and Andrew D. Johnson and Zolt{\'a}n Kutalik and Albert Vernon Smith and Julia Zhuo Shi and Maksim V. Struchalin and Rita P. S. Middelberg and Morris J. Brown and Angelo L. Gaffo and Nicola Pirastu and Guo Li and Caroline Hayward and Tatijana Zemunik and Jennifer E. Huffman and Loic Yengo and Jing Hua Zhao and Ayşe Demirkan and Mary F. Feitosa and Xuan Liu and Giovanni Malerba and Lorna M. Lopez and Pim van der Harst and Xinzhong Li and Marcus Edi Kleber and Andrew A. Hicks and Ilja Maria Nolte and {\AA}sa Johansson and Federico Murgia and Sarah H. Wild and Stephan J. L. Bakker and John F. Peden and Abbas Dehghan and Maristella Steri and Albert Tenesa and Vasiliki Lagou and Perttu P. Salo and Massimo Mangino and Lynda M Rose and Terho Lehtim{\"a}ki and Owen M. Woodward and Yukinori Okada and Adrienne Tin and Christian M{\"u}ller and Christopher Oldmeadow and Margus Putku and Darina Czamara and Peter Kraft and Laura Frogheri and Gian Andri Thun and Anne Grotevendt and Gauti Kjartan G{\'i}slason and Tamara B. Harris and Lenore J. Launer and Patrick F. McArdle and Alan R. Shuldiner and Eric Boerwinkle and Josef Coresh and Helena Schmidt and Michael Schallert and Nicholas G. Martin and Grant W. Montgomery and Michiaki Kubo and Yusuke Nakamura and Toshihiro Tanaka and Patricia B. Munroe and Nilesh J. Samani and David R. Jacobs and Kiang Liu and Pio D'Adamo and Sheila Ulivi and Jerome I. Rotter and Bruce M. Psaty and Peter Vollenweider and G{\'e}rard Waeber and Susan Campbell and Olivier Devuyst and Pau Navarro and Ivana Kol{\vc}i{\'c} and Nicholas D. Hastie and Beverley Balkau and Philippe Froguel and T{\~o}nu Esko and Andres Salumets and Kay-Tee Khaw and Claudia Langenberg and Nicholas J. Wareham and Aaron Isaacs and Aldi T. Kraja and Qunyuan Zhang and Philipp S. Wild and Rodney J. Scott and Elizabeth G. Holliday and Elin Org and Margus Viigimaa and Stefania Bandinelli and Jeffrey E. Metter and Antonio Lupo and Elisabetta Trabetti and Rossella Sorice and Angela D{\"o}ring and Eva Lattka and Konstantin Strauch and Fabian J Theis and Melanie Waldenberger and Heinz-Erich Wichmann and Gail Davies and Alan J. Gow and Marcel Bruinenberg and Ronald P Stolk and Jaspal S. Kooner and Weihua Zhang and Bernhard R. Winkelmann and Bernhard Otto Boehm and Susanne Lucae and Brenda W.J.H. Penninx and Johannes H. Smit and Gary C Curhan and Poorva Mudgal and Robert M. Plenge and Laura Portas and Ivana Persico and Mirna Abaffy Kirin and James F. Wilson and Irene Mateo Leach and Wiek H. van Gilst and Anuj Goel and Halit Ongen and Albert Hofman and Fernando Rivadeneira and Andr{\'e} G. Uitterlinden and Medea Imboden and Arnold von Eckardstein and Francesco Cucca and Ramaiah Nagaraja and Maria Grazia Piras and Matthias Nauck and Claudia Schurmann and Kathrin Budde and Florian D. Ernst and Susan M. Farrington and Evropi Theodoratou and Inga Prokopenko and Michael Stumvoll and Antti M. Jula and Markus Perola and Veikko V Salomaa and So-Youn Shin and Tim D. Spector and Cinzia Felicita Sala and Paul M. Ridker and Mika K{\"a}h{\"o}nen and Jorma S.A. Viikari and Christian Hengstenberg and Christopher P. Nelson and James F. Meschia and Mike A. Nalls and Pankaj Sharma and Andrew B. Singleton and Naoyuki Kamatani and Tanja Zeller and Michel Burnier and John Richard Attia and Maris Laan and Norman Klopp and Hans L. Hillege and Stefan Kloiber and Hyon K. Choi and Mario Pirastu and Silvia Tore and Nicole Probst-Hensch and Henry V{\"o}lzke and Vilmundur G. Gudnason and Afshin Parsa and Reinhold Schmidt and John B. Whitfield and Myriam Fornage and Paolo Gasparini and David S. Siscovick and Ozren Pola{\vs}ek and Harry Campbell and Igor Rudan and Nabila Bouatia-Naji and Andres Metspalu and Ruth J. F. Loos and Cornelia van Duijn and Ingrid B. Borecki and Luigi Ferrucci and Giovanni Gambaro and Ian J. Deary and Bruce H. R. Wolffenbuttel and John C. Chambers and Winfried M{\"a}rz and Peter Paul Pramstaller and Harold Snieder and Ulf Gyllensten and Alan F. Wright and Gerjan J Navis and Hugh C. Watkins and Jacqueline C. M. Witteman and Serena Sanna and Sabine Schipf and Malcolm G. Dunlop and Anke Tönjes and Samuli Ripatti and Nicole Soranzo and Daniela Toniolo and Daniel I. Chasman and Olli T. Raitakari and Wen Kao and Marina Ciullo and Caroline S. Fox and Mark J. Caulfield and Murielle Bochud and Christian Gieger},
  journal={Nature Genetics},
Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4… 

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

A trans-ancestry genome-wide association study of serum urate levels identifies 183 loci that improve the prediction of gout in an independent cohort of 334,880 individuals, and implicates the kidney and liver as key target organs and prioritize potential causal genes.

Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus

Serum urate concentration can be studied in large datasets to find genetic and epigenetic loci that may be related to cardiometabolic traits and EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control.

Trans-ancestral meta-analysis using data from European and East Asian populations to identify ten new loci for serum urate levels and identifies candidate causal genes at 24 loci and a network of previously unidentified genes likely involved in control of serum Urate levels, further illuminating the molecular mechanisms of urate control.

Genome-wide association analysis identifies three new risk loci for gout arthritis in Han Chinese

A multistage genome-wide association study in a Han Chinese population is conducted and three novel loci likely associated with the progression from hyperuricemia to gout are identified, suggesting new insights into the pathogenesis of gout arthritis.

Common UCP2 variants contribute to serum urate concentrations and the risk of hyperuricemia

A novel gene is identified, UCP2, that influences the serum urate concentration and the risk of hyperuricemia and the degree of association varies with gender and BMI levels.

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes

A genome-wide association study of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific, and this work leads to a novel concept for the therapeutic target of g out/hyperuricaemia.

Refining genome-wide associated loci for serum uric acid in individuals with African ancestry.

This first GWAS of serum uric acid in continental Africans identified three associations at two loci, SLC2A9 and SLC22A12, which accounted for 4.3% of the variance of serum Uric acid.

Fine mapping and identification of serum urate loci in American Indians: The Strong Heart Family Study

The results demonstrate the association ofSU with uric acid transporters in a minority population of American Indians and potential novel associations of SU with neuronal-related genes which warrant further investigation.

Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes

It is demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type) and the effect of the risk allele of each SNP on clinical parameters showed significant linear relationships.

A genome-wide association analysis of 2,622,830 individuals reveals new pathogenic pathways in gout.

New insights into the molecular pathogenesis of gout are provided and strong candidate immune genes involved in epigenetic remodelling, cell osmolarity, and regulation of NLRP3-inflammasome activity are identified.



Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele.

The data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants and in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA.

Meta-Analysis of Genome-Wide Association Studies in >80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels

A genome-wide association analysis of CRP identified 18 loci that were associated with CRP levels and highlighted immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.

Multiple Genetic Loci Influence Serum Urate Levels and Their Relationship With Gout and Cardiovascular Disease Risk Factors

The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum Urate and cardiovascular risk factors and coronary heart disease (CHD).

Genome-wide association study for C-reactive protein levels identified pleiotropic associations in the IL6 locus.

The pivotal role of the IL6 locus in the regulation of serum CRP levels and inflammatory pathways is demonstrated, and a single nucleotide polymorphism in the promoter region of interleukin-6 (IL6) is identified.

Identification of low-frequency variants associated with gout and serum uric acid levels

This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits, as well as a common variant previously associated with serum uric acid levels.

Meta-Analysis of 28,141 Individuals Identifies Common Variants within Five New Loci That Influence Uric Acid Concentrations

The hypothesis that transport proteins are key in regulating serum uric acid levels is supported, as 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance were identified, five of which are novel.

Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout

This study shows using functional assays that human ATP-binding cassette, subfamily G, 2 (ABCG2), encoded by the ABCG2 gene contained in this region, is a hitherto unknown urate efflux transporter and supports the common disease-common variant hypothesis in the etiology of gout.

A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease

A genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD) led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31.