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PMID: 20037589 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Twin Study

A genome-wide perspective of genetic variation in human metabolism.

Nature genetics ·Vol. 42 ·No. 2 ·2010-02-00 ·Pages 137-41

Illig T, Gieger C, Zhai G, Römisch-Margl W, Wang-Sattler R, Prehn C, Altmaier E, Kastenmüller G, Kato BS, Mewes HW, Meitinger T, de Angelis MH, Kronenberg F, Soranzo N, Wichmann HE, Spector TD, Adamski J, Suhre K

Abstract

Serum metabolite concentrations provide a direct readout of biological processes in the human body, and they are associated with disorders such as cardiovascular and metabolic diseases. We present a genome-wide association study (GWAS) of 163 metabolic traits measured in human blood from 1,809 participants from the KORA population, with replication in 422 participants of the TwinsUK cohort. For eight out of nine replicated loci (FADS1, ELOVL2, ACADS, ACADM, ACADL, SPTLC3, ETFDH and SLC16A9), the genetic variant is located in or near genes encoding enzymes or solute carriers whose functions match the associating metabolic traits. In our study, the use of metabolite concentration ratios as proxies for enzymatic reaction rates reduced the variance and yielded robust statistical associations with P values ranging from 3 x 10(-24) to 6.5 x 10(-179). These loci explained 5.6%-36.3% of the observed variance in metabolite concentrations. For several loci, associations with clinically relevant parameters have been reported previously.

MeSH Terms
Delta-5 Fatty Acid Desaturase Genetic Loci/genetics Genetic Variation Genome, Human/genetics Genome-Wide Association Study Humans Metabolome/genetics Polymorphism, Single Nucleotide/genetics Reproducibility of Results United Kingdom
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Illig Thomas
Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Gieger Christian
Zhai Guangju
Römisch-Margl Werner
Wang-Sattler Rui
Prehn Cornelia
Altmaier Elisabeth
Kastenmüller Gabi
Kato Bernet S
Mewes Hans-Werner
Meitinger Thomas
de Angelis Martin Hrabé
Kronenberg Florian
Soranzo Nicole
Wichmann H-Erich
Spector Tim D
Adamski Jerzy
Suhre Karsten
References (28)
28 references, click to expand
  1. Identification of four new mutations in the short-chain acyl-CoA dehydrogenase (SCAD) gene in two patients: one of the variant alleles, 511C-->T, is present at an unexpectedly high frequency in the general population, as was the case for 625G-->A, together conferring susceptibility to ethylmalonic aciduria.
    Hum Mol Genet. 1998 Apr;7(4):619-27 PMID: 9499414
  2. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism.
    Cell. 2008 Sep 19;134(6):933-44 PMID: 18805087
  3. The emerging field of lipidomics.
    Nat Rev Drug Discov. 2005 Jul;4(7):594-610 PMID: 16052242
  4. Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients.
    PLoS One. 2008;3(12):e4003 PMID: 19104657
  5. The frequency of short-chain acyl-CoA dehydrogenase gene variants in the US population and correlation with the C(4)-acylcarnitine concentration in newborn blood spots.
    Mol Genet Metab. 2003 Apr;78(4):239-46 PMID: 12706374
  6. V490M, a common mutation in 3-phosphoglycerate dehydrogenase deficiency, causes enzyme deficiency by decreasing the yield of mature enzyme.
    J Biol Chem. 2002 Mar 1;277(9):7136-43 PMID: 11751922
  7. Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.
    PLoS Genet. 2008 Nov;4(11):e1000282 PMID: 19043545
  8. Are twins and singletons comparable? A study of disease-related and lifestyle characteristics in adult women.
    Twin Res. 2001 Dec;4(6):464-77 PMID: 11780939
  9. KORA-gen--resource for population genetics, controls and a broad spectrum of disease phenotypes.
    Gesundheitswesen. 2005 Aug;67 Suppl 1:S26-30 PMID: 16032514
  10. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.
    Nat Genet. 2009 Jan;41(1):47-55 PMID: 19060911
  11. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans.
    Nat Genet. 2008 Feb;40(2):189-97 PMID: 18193044
  12. Thermolabile phenotype of carnitine palmitoyltransferase II variations as a predisposing factor for influenza-associated encephalopathy.
    FEBS Lett. 2005 Apr 11;579(10):2040-4 PMID: 15811315
  13. Metabolic profiling reveals distinct variations linked to nicotine consumption in humans--first results from the KORA study.
    PLoS One. 2008;3(12):e3863 PMID: 19057651
  14. A new multipoint method for genome-wide association studies by imputation of genotypes.
    Nat Genet. 2007 Jul;39(7):906-13 PMID: 17572673
  15. Newly identified loci that influence lipid concentrations and risk of coronary artery disease.
    Nat Genet. 2008 Feb;40(2):161-9 PMID: 18193043
  16. The common P446L polymorphism in GCKR inversely modulates fasting glucose and triglyceride levels and reduces type 2 diabetes risk in the DESIR prospective general French population.
    Diabetes. 2008 Aug;57(8):2253-7 PMID: 18556336
  17. Functional variants of OCTN cation transporter genes are associated with Crohn disease.
    Nat Genet. 2004 May;36(5):471-5 PMID: 15107849
  18. Common variants at 30 loci contribute to polygenic dyslipidemia.
    Nat Genet. 2009 Jan;41(1):56-65 PMID: 19060906
  19. Variants in MTNR1B influence fasting glucose levels.
    Nat Genet. 2009 Jan;41(1):77-81 PMID: 19060907
  20. Multiple loci associated with indices of renal function and chronic kidney disease.
    Nat Genet. 2009 Jun;41(6):712-7 PMID: 19430482
  21. The association of desaturase 9 and plasma fatty acid composition with insulin resistance-associated factors in female adolescents.
    Metabolism. 2009 Feb;58(2):158-66 PMID: 19154947
  22. Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study.
    PLoS Genet. 2009 Jan;5(1):e1000338 PMID: 19148276
  23. [Metabolomics in diagnosing metabolic diseases].
    Ther Umsch. 2008 Sep;65(9):487-91 PMID: 18791962
  24. Moderation of breastfeeding effects on the IQ by genetic variation in fatty acid metabolism.
    Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18860-5 PMID: 17984066
  25. Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma homocysteine in a healthy population: a genome-wide evaluation of 13 974 participants in the Women's Genome Health Study.
    Circ Cardiovasc Genet. 2009 Apr;2(2):142-50 PMID: 20031578
  26. Association of fatty acid desaturase genes with attention-deficit/hyperactivity disorder.
    Biol Psychiatry. 2006 Nov 15;60(10):1053-61 PMID: 16893529
  27. Bioinformatics analysis of targeted metabolomics--uncovering old and new tales of diabetic mice under medication.
    Endocrinology. 2008 Jul;149(7):3478-89 PMID: 18372322
  28. Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.
    Nat Genet. 2009 Jan;41(1):35-46 PMID: 19060910
Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.507
Published
2010-02-00
Epub
2009-00-27
Pages
137-41
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC3773904
Subset
IM
Grants
Wellcome Trust · 091746 · United Kingdom
Biotechnology and Biological Sciences Research Council · G20234 · United Kingdom
Corrections
CommentIn
PMID: 20104246
External Links
PubMed source DOI: 10.1038/ng.507 PMC Full Text View journal details
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