title: Novel genetic associations with serum level metabolites identified by phenotype set enrichment analyses.
abstract: Availability of standardized metabolite panels and genome-wide single-nucleotide polymorphism data endorse the comprehensive analysis of gene-metabolite association. Currently, many studies use genome-wide association analysis to investigate the genetic effects on single metabolites (mGWAS) separately. Such studies have identified several loci that are associated not only with one but with multiple metabolites, facilitated by the fact that metabolite panels often include metabolites of the same or related pathways. Strategies that analyse several phenotypes in a combined way were shown to be able to detect additional genetic loci. One of those methods is the phenotype set enrichment analysis (PSEA) that tests sets of metabolites for enrichment at genes. Here we applied PSEA on two different panels of serum metabolites together with genome-wide data. All analyses were performed as a two-step identification-validation approach, using data from the population-based KORA cohort and the TwinsUK study. In addition to confirming genes that were already known from mGWAS, we were able to identify and validate 12 new genes. Knowledge about gene function was supported by the enriched metabolite sets. For loci with unknown gene functions, the results suggest a function that is interrelated with the metabolites, and hint at the underlying pathways.
authors.affiliation: Institute of Genetic Epidemiology, janina.ried@helmholtz-muenchen.de.
authors.forename: Janina S
authors.initials: JS
authors.lastname: Ried
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, CB10 1HH Hinxton, UK, MRC Integrative Epidemiology Unit, University of Bristol, BS8 2BN Bristol, UK.
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Shin
authors.affiliation: Institute of Computational Biology.
authors.forename: Jan
authors.initials: J
authors.lastname: Krumsiek
authors.affiliation: Research Unit of Molecular Epidemiology, Hannover Unified Biobank, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.affiliation: Institute of Computational Biology, Department of Mathematics, Technische Universität München, 85748 Garching, Germany.
authors.forename: Fabian J
authors.initials: FJ
authors.lastname: Theis
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London School of Medicine, St Thomas' Hospital, SE1 7EH London, UK.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Institute of Experimental Genetics, Genome Analysis Center, Institute of Experimental Genetics, Life and Food Science Center Weihenstephan, Technische Universität München, 85354 Freising-Weihenstephan, Germany, German Center for Diabetes Research, 85764 Neuherberg, Germany.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.affiliation: Institute of Epidemiology I and Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology and , Klinikum Grosshadern, 81377 Munich, Germany and.
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.affiliation: Institute of Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, 81377 Munich, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, CB10 1HH Hinxton, UK.
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany, Department of Physiology and Biophysics, Weill Cornell Medical College, PO Box 24144 Doha, Qatar.
authors.forename: Karsten
authors.initials: K
authors.lastname: Suhre
authors.affiliation: Institute of Genetic Epidemiology.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
mesh_terms: D015415:Biomarkers / Q000097:blood*; D015331:Cohort Studies; D019295:Computational Biology; D056726:Genetic Association Studies; D056426:Genetic Loci; D005838:Genotype; D006801:Humans; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results
chemical_list: D015415:Biomarkers