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PMID: 21983786 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

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

Nature genetics ·Vol. 43 ·No. 11 ·2011-10-09 ·Pages 1127-30

Sulem P, Gudbjartsson DF, Walters GB, Helgadottir HT, Helgason A, Gudjonsson SA, Zanon C, Besenbacher S, Bjornsdottir G, Magnusson OT, Magnusson G, Hjartarson E, Saemundsdottir J, Gylfason A, Jonasdottir A, Holm H, Karason A, Rafnar T, Stefansson H, Andreassen OA, Pedersen JH, Pack AI, de Visser MC, Kiemeney LA, Geirsson AJ, Eyjolfsson GI, Olafsson I, Kong A, Masson G, Jonsson H, Thorsteinsdottir U, Jonsdottir I, Stefansson K

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.

MeSH Terms
Gout/genetics Humans Iceland Mutation, Missense Polymorphism, Single Nucleotide Uric Acid/blood
Chemicals
Uric Acid
Authors & Affiliations
33 authors, click to expand affiliations / ORCID
Sulem Patrick
deCODE genetics, Reykjavik, Iceland. patrick.sulem@decode.is
Gudbjartsson Daniel F
Walters G Bragi
Helgadottir Hafdis T
Helgason Agnar
Gudjonsson Sigurjon A
Zanon Carlo
Besenbacher Soren
Bjornsdottir Gyda
Magnusson Olafur T
Magnusson Gisli
Hjartarson Eirikur
Saemundsdottir Jona
Gylfason Arnaldur
Jonasdottir Adalbjorg
Holm Hilma
Karason Ari
Rafnar Thorunn
Stefansson Hreinn
Andreassen Ole A
Pedersen Jesper H
Pack Allan I
de Visser Marieke C H
Kiemeney Lambertus A
Geirsson Arni J
Eyjolfsson Gudmundur I
Olafsson Isleifur
Kong Augustine
Masson Gisli
Jonsson Helgi
Thorsteinsdottir Unnur
Jonsdottir Ingileif
Stefansson Kari
References (30)
30 references, click to expand
  1. Role of human aldehyde dehydrogenases in endobiotic and xenobiotic metabolism.
    Drug Metab Rev. 2004 May;36(2):279-99 PMID: 15237855
  2. Segregation analysis of serum uric acid in the NHLBI Family Heart Study.
    Hum Genet. 2000 Mar;106(3):355-9 PMID: 10798367
  3. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.
    Nat Genet. 2008 Apr;40(4):437-42 PMID: 18327257
  4. The Danish randomized lung cancer CT screening trial--overall design and results of the prevalence round.
    J Thorac Oncol. 2009 May;4(5):608-14 PMID: 19357536
  5. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke.
    Nat Genet. 2003 Oct;35(2):131-8 PMID: 14517540
  6. Effect of ethanol on metabolism of purine bases (hypoxanthine, xanthine, and uric acid).
    Clin Chim Acta. 2005 Jun;356(1-2):35-57 PMID: 15936302
  7. Analysis of the genotypes for aldehyde dehydrogenase 2 in Japanese patients with primary gout.
    Adv Exp Med Biol. 1994;370:53-6 PMID: 7660963
  8. Sequence variant on 8q24 confers susceptibility to urinary bladder cancer.
    Nat Genet. 2008 Nov;40(11):1307-12 PMID: 18794855
  9. SLC2A9 influences uric acid concentrations with pronounced sex-specific effects.
    Nat Genet. 2008 Apr;40(4):430-6 PMID: 18327256
  10. Gout and hyperuricemia.
    Am Fam Physician. 1999 Feb 15;59(4):925-34 PMID: 10068714
  11. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout.
    Rheumatology (Oxford). 2007 Aug;46(8):1372-4 PMID: 17522099
  12. Fast and accurate short read alignment with Burrows-Wheeler transform.
    Bioinformatics. 2009 Jul 15;25(14):1754-60 PMID: 19451168
  13. Common variants conferring risk of schizophrenia.
    Nature. 2009 Aug 6;460(7256):744-7 PMID: 19571808
  14. Detection of sharing by descent, long-range phasing and haplotype imputation.
    Nat Genet. 2008 Sep;40(9):1068-75 PMID: 19165921
  15. A novel endonuclease IV post-PCR genotyping system.
    Nucleic Acids Res. 2006;34(19):e128 PMID: 17012270
  16. A rare variant in MYH6 is associated with high risk of sick sinus syndrome.
    Nat Genet. 2011 Mar 06;43(4):316-20 PMID: 21378987
  17. Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.
    Am J Hum Genet. 2008 Jan;82(1):139-49 PMID: 18179892
  18. Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations.
    PLoS Genet. 2009 Jun;5(6):e1000504 PMID: 19503597
  19. Analysis and update of the human aldehyde dehydrogenase (ALDH) gene family.
    Hum Genomics. 2005 Jun;2(2):138-43 PMID: 16004729
  20. The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts.
    PLoS Genet. 2007 Nov;3(11):e194 PMID: 17997608
  21. Pathogenesis of gout.
    Ann Intern Med. 2005 Oct 4;143(7):499-516 PMID: 16204163
  22. GeneNote: whole genome expression profiles in normal human tissues.
    C R Biol. 2003 Oct-Nov;326(10-11):1067-72 PMID: 14744114
  23. Linkage disequilibrium analysis in young populations: pseudo-vitamin D-deficiency rickets and the founder effect in French Canadians.
    Am J Hum Genet. 1996 Sep;59(3):633-43 PMID: 8751865
  24. Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily.
    Expert Opin Drug Metab Toxicol. 2008 Jun;4(6):697-720 PMID: 18611112
  25. Heritability of cardiovascular and personality traits in 6,148 Sardinians.
    PLoS Genet. 2006 Aug 25;2(8):e132 PMID: 16934002
  26. Gout epidemiology: results from the UK General Practice Research Database, 1990-1999.
    Ann Rheum Dis. 2005 Feb;64(2):267-72 PMID: 15647434
  27. Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors.
    Circ Cardiovasc Genet. 2010 Dec;3(6):523-30 PMID: 20884846
  28. Genetics of gout.
    Curr Opin Rheumatol. 2010 Mar;22(2):144-51 PMID: 20110790
  29. Estimating allele age.
    Annu Rev Genomics Hum Genet. 2000;1:225-49 PMID: 11701630
  30. A new multipoint method for genome-wide association studies by imputation of genotypes.
    Nat Genet. 2007 Jul;39(7):906-13 PMID: 17572673
Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.972
Email
patrick.sulem@decode.is
Published
2011-10-09
Epub
2011-00-09
Pages
1127-30
Language
English
Region
United States
NLM ID
9216904
Subset
IM
External Links
PubMed source DOI: 10.1038/ng.972 View journal details
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