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Nature. 2011 Aug 31;477(7362):54-60. doi: 10.1038/nature10354.

Human metabolic individuality in biomedical and pharmaceutical research.

Collaborators (210)

Kathiresan S, Reilly MP, Samani NJ, Schunkert H, Erdmann J, Assimes TL, Boerwinkle E, Erdmann J, Hall A, Hengstenberg C, Kathiresan S, König IR, Laaksonen R, McPherson R, Reilly MP, Samani NJ, Schunkert H, Thompson JR, Thorsteinsdottir U, Ziegler A, König IR, Thompson JR, Absher D, Chen L, Cupples LA, Halperin E, Li M, Musunuru K, Preuss M, Schillert A, Thorleifsson G, Voight BF, Wells GA, Absher D, Assimes TL, Deloukas P, Erdmann J, Holm H, Kathiresan S, König IR, McPherson R, Reilly MP, Roberts R, Samani NJ, Schunkert H, Stewart AF, Fortmann S, Go A, Hlatky M, Iribarren C, Knowles J, Myers R, Quertermous T, Sidney S, Risch N, Tang H, Blankenberg S, Zeller T, Schillert A, Wild P, Ziegler A, Schnabel R, Sinning C, Lackner K, Tiret L, Nicaud V, Cambien F, Bickel C, Rupprecht HJ, Perret C, Proust C, Münzel T, Barbalic M, Bis J, Boerwinkle E, Chen IY, Cupples LA, Dehghan A, Demissie-Banjaw S, Folsom A, Glazer N, Gudnason V, Harris T, Heckbert S, Levy D, Lumley T, Marciante K, Morrison A, O'Donnell CJ, Psaty BM, Rice K, Rotter JI, Siscovick DS, Smith N, Smith A, Taylor KD, van Duijn C, Volcik K, Whitteman J, Ramachandran V, Hofman A, Uitterlinden A, Gretarsdottir S, Gulcher JR, Holm H, Kong A, Stefansson K, Thorgeirsson G, Andersen K, Thorleifsson G, Thorsteinsdottir U, Erdmann J, Fischer M, Grosshennig A, Hengstenberg C, König IR, Lieb W, Linsel-Nitschke P, Preuss M, Stark K, Schreiber S, Wichmann HE, Ziegler A, Schunkert H, Aherrahrou Z, Bruse P, Doering A, Erdmann J, Hengstenberg C, Illig T, Klopp N, König IR, Linsel-Nitschke P, Loley C, Medack A, Meisinger C, Meitinger T, Nahrstedt J, Peters A, Preuss M, Stark K, Wagner AK, Wichmann HE, Willenborg C, Ziegler A, Schunkert H, Böhm BO, Dobnig H, Grammer TB, Halperin E, Hoffmann MM, Kleber M, Laaksonen R, März W, Meinitzer A, Winkelmann BR, Pilz S, Renner W, Scharnagl H, Stojakovic T, Tomaschitz A, Winkler K, Voight BF, Musunuru K, Guiducci C, Burtt N, Gabriel SB, Siscovick DS, O'Donnell CJ, Elosua R, Peltonen L, Salomaa V, Schwartz SM, Melander O, Altshuler D, Kathiresan S, Stewart AF, Chen L, Dandona S, Wells GA, Jarinova O, McPherson R, Roberts R, Reilly MP, Li M, Qu L, Wilensky R, Matthai W, Hakonarson HH, Devaney J, Burnett MS, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Knouff CW, Waterworth DM, Walker MC, Mooser V, Epstein SE, Rader DJ, Samani NJ, Thompson JR, Braund PS, Nelson CP, Wright BJ, Balmforth AJ, Ball SG, Hall AS.

Author information

1
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
2
Faculty of Biology, Ludwig-Maximilians-Universität, Planegg-Martinsried, Germany.
3
Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Education City - Qatar Foundation, Doha, Qatar.
4
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton UK.
5
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
6
Metabolon Inc., Durham, North Carolina, USA.
7
School of Life Sciences, Oxford Brookes University, Headington, Oxford, UK.
8
Department of Genome-oriented Bioinformatics, Life and Food Science Center Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany.
9
Universität zu Lübeck, Medizinische Klinik II, Lübeck, Germany.
10
Department of Twin Research & Genetic Epidemiology, King's College London, UK.
11
Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
12
Institute of Experimental Genetics, Life and Food Science Center Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany.
13
Renal Division, University Hospital Freiburg, Germany.
14
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria.
15
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
16
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
17
Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
18
Department of Cardiovascular Sciences, University of Leicester, and Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK.
19
Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
20
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
21
Klinikum Grosshadern, Munich, Germany.
22
Unit for Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
#
Contributed equally

Abstract

Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.

PMID:
21886157
PMCID:
PMC3832838
DOI:
10.1038/nature10354
[Indexed for MEDLINE]
Free PMC Article

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