Abstract

We tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. We identified a low-frequency missense variant (c.1580C>G) in ALDH16A1 associated with gout (OR = 3.12, P = 1.5 × 10−16, at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 × 10−21). We confirmed the association with gout by performing Sanger sequencing on 6,017 Icelanders. The association with gout was stronger in males relative to females. We also found a second variant on chromosome 1 associated with gout (OR = 1.92, P = 0.046, at-risk allele frequency = 0.986) and serum uric acid levels (effect = 0.48 s.d., P = 4.5 × 10−16). This variant is close to a common variant previously associated with serum uric acid levels. This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits.

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NCBI Reference Sequence

References

  1. 1.

    , & Pathogenesis of gout. Ann. Intern. Med. 143, 499–516 (2005).

  2. 2.

    et al. Gout epidemiology: results from the UK General Practice Research Database, 1990–1999. Ann. Rheum. Dis. 64, 267–272 (2005).

  3. 3.

    et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford) 46, 1372–1374 (2007).

  4. 4.

    et al. SLC2A9 influences uric acid concentrations with pronounced sex-specific effects. Nat. Genet. 40, 430–436 (2008).

  5. 5.

    et al. The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts. PLoS Genet. 3, e194 (2007).

  6. 6.

    et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat. Genet. 40, 437–442 (2008).

  7. 7.

    et al. Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am. J. Hum. Genet. 82, 139–149 (2008).

  8. 8.

    et al. Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations. PLoS Genet. 5, e1000504 (2009).

  9. 9.

    et al. Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. Circ. Cardiovasc. Genet. 3, 523–530 (2010).

  10. 10.

    et al. Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet. 2, e132 (2006).

  11. 11.

    et al. Segregation analysis of serum uric acid in the NHLBI Family Heart Study. Hum. Genet. 106, 355–359 (2000).

  12. 12.

    et al. Detection of sharing by descent, long-range phasing and haplotype imputation. Nat. Genet. 40, 1068–1075 (2008).

  13. 13.

    , , & Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily. Expert Opin. Drug Metab. Toxicol. 4, 697–720 (2008).

  14. 14.

    et al. GeneNote: whole genome expression profiles in normal human tissues. C. R. Biol. 326, 1067–1072 (2003).

  15. 15.

    & Analysis and update of the human aldehyde dehydrogenase (ALDH) gene family. Hum. Genomics 2, 138–143 (2005).

  16. 16.

    , & Role of human aldehyde dehydrogenases in endobiotic and xenobiotic metabolism. Drug Metab. Rev. 36, 279–299 (2004).

  17. 17.

    , & Effect of ethanol on metabolism of purine bases (hypoxanthine, xanthine, and uric acid). Clin. Chim. Acta 356, 35–57 (2005).

  18. 18.

    et al. Analysis of the genotypes for aldehyde dehydrogenase 2 in Japanese patients with primary gout. Adv. Exp. Med. Biol. 370, 53–56 (1994).

  19. 19.

    , & Genetics of gout. Curr. Opin. Rheumatol. 22, 144–151 (2010).

  20. 20.

    et al. A rare variant in MYH6 is associated with high risk of sick sinus syndrome. Nat. Genet. 43, 316–320 (2011).

  21. 21.

    & Estimating allele age. Annu. Rev. Genomics Hum. Genet. 1, 225–249 (2000).

  22. 22.

    et al. Linkage disequilibrium analysis in young populations: pseudo-vitamin D-deficiency rickets and the founder effect in French Canadians. Am. J. Hum. Genet. 59, 633–643 (1996).

  23. 23.

    , & Gout and hyperuricemia. Am. Fam. Physician 59, 925–934 (1999).

  24. 24.

    et al. The Danish randomized lung cancer CT screening trial—overall design and results of the prevalence round. J. Thorac. Oncol. 4, 608–614 (2009).

  25. 25.

    et al. Common variants conferring risk of schizophrenia. Nature 460, 744–747 (2009).

  26. 26.

    et al. Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nat. Genet. 40, 1307–1312 (2008).

  27. 27.

    et al. A novel endonuclease IV post-PCR genotyping system. Nucleic Acids Res. 34, e128 (2006).

  28. 28.

    & Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

  29. 29.

    , , , & A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

  30. 30.

    et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat. Genet. 35, 131–138 (2003).

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Acknowledgements

This project was supported by a European Commission Framework 7 Programme grant (200800 TREAT-OA, Translational Research in Europa–Applied Technologies for Osteoarthritis).

Author information

Author notes

    • Patrick Sulem
    • , Daniel F Gudbjartsson
    •  & G Bragi Walters

    These authors contributed equally to this work.

Affiliations

  1. deCODE genetics, Reykjavik, Iceland.

    • Patrick Sulem
    • , Daniel F Gudbjartsson
    • , G Bragi Walters
    • , Hafdis T Helgadottir
    • , Agnar Helgason
    • , Sigurjon A Gudjonsson
    • , Carlo Zanon
    • , Soren Besenbacher
    • , Gyda Bjornsdottir
    • , Olafur T Magnusson
    • , Gisli Magnusson
    • , Eirikur Hjartarson
    • , Jona Saemundsdottir
    • , Arnaldur Gylfason
    • , Adalbjorg Jonasdottir
    • , Hilma Holm
    • , Ari Karason
    • , Thorunn Rafnar
    • , Hreinn Stefansson
    • , Augustine Kong
    • , Gisli Masson
    • , Unnur Thorsteinsdottir
    • , Ingileif Jonsdottir
    •  & Kari Stefansson
  2. Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

    • Ole A Andreassen
  3. Department of Cardiothoracic Surgery, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

    • Jesper H Pedersen
  4. Center for Sleep and Circardian Neurobiology, Division of Sleep Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Allan I Pack
  5. Department of Epidemiology, Biostatistics & Health Technology Assessment, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Marieke C H de Visser
    •  & Lambertus A Kiemeney
  6. Comprehensive Cancer Center East (IKO), Nijmegen, The Netherlands.

    • Lambertus A Kiemeney
  7. Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Lambertus A Kiemeney
  8. Landspitali, The National University Hospital of Iceland, Department of Medicine, Reykjavik, Iceland.

    • Arni J Geirsson
    •  & Helgi Jonsson
  9. Icelandic Medical Center (Laeknasetrid) Laboratory in Mjodd (RAM), Reykjavik, Iceland.

    • Gudmundur I Eyjolfsson
  10. Landspitali, The National University Hospital of Iceland, Department of Clinical Biochemistry, Reykjavik, Iceland.

    • Isleifur Olafsson
  11. University of Iceland, Faculty of Medicine, Reykjavik, Iceland.

    • Helgi Jonsson
    • , Unnur Thorsteinsdottir
    • , Ingileif Jonsdottir
    •  & Kari Stefansson
  12. Landspitali, The National University Hospital of Iceland, Department of Immunology, Reykjavik, Iceland.

    • Ingileif Jonsdottir

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Contributions

P.S., D.F.G., G.B.W., H.J., U.T., I.J. and K.S. wrote the manuscript. P.S., D.F.G., G.B.W., G.B., H.H., H.J., U.T., I.J. and K.S. designed the study. A. Karason, T.R., H.S., O.A.A., J.H.P., A.I.P., M.C.H.d.V., L.A.K., A.J.G., G.I.E., I.O., H.J. and I.J. recruited participants for the study and collected clinical or paraclinical information. P.S., D.F.G., G.B.W., A.H., S.B., A.G., A. Kong and G. Masson performed statistical analyses. S.A.G. and C.Z. performed bioinformatics analyses. O.T.M., G. Magnusson, E.H., J.S., A.J. and G. Masson generated, processed and managed data for the whole-genome sequencing project. H.T.H. performed genotype and sequence calling.

Competing interests

Some of the authors employed by deCODE genetics own stock or stock options in the company.

Corresponding authors

Correspondence to Patrick Sulem or Kari Stefansson.

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https://doi.org/10.1038/ng.972

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