title: Nonadditive Effects of Genes in Human Metabolomics.
abstract: Genome-wide association studies (GWAS) are widely applied to analyze the genetic effects on phenotypes. With the availability of high-throughput technologies for metabolite measurements, GWAS successfully identified loci that affect metabolite concentrations and underlying pathways. In most GWAS, the effect of each SNP on the phenotype is assumed to be additive. Other genetic models such as recessive, dominant, or overdominant were considered only by very few studies. In contrast to this, there are theories that emphasize the relevance of nonadditive effects as a consequence of physiologic mechanisms. This might be especially important for metabolites because these intermediate phenotypes are closer to the underlying pathways than other traits or diseases. In this study we analyzed systematically nonadditive effects on a large panel of serum metabolites and all possible ratios (22,801 total) in a population-based study [Cooperative Health Research in the Region of Augsburg (KORA) F4, N = 1,785]. We applied four different 1-degree-of-freedom (1-df) tests corresponding to an additive, dominant, recessive, and overdominant trait model as well as a genotypic model with two degree-of-freedom (2-df) that allows a more general consideration of genetic effects. Twenty-three loci were found to be genome-wide significantly associated (Bonferroni corrected P ≤ 2.19 × 10(-12)) with at least one metabolite or ratio. For five of them, we show the evidence of nonadditive effects. We replicated 17 loci, including 3 loci with nonadditive effects, in an independent study (TwinsUK, N = 846). In conclusion, we found that most genetic effects on metabolite concentrations and ratios were indeed additive, which verifies the practice of using the additive model for analyzing SNP effects on metabolites.
authors.affiliation: Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia Novosibirsk State University, 630090 Novosibirsk, Russia Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Yakov A
authors.initials: YA
authors.lastname: Tsepilov
authors.affiliation: Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, CB10 1HH, United Kingdom MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, BS8 1TH, United Kingdom.
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Shin
authors.affiliation: Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, CB10 1HH, United Kingdom Department of Haematology, University of Cambridge, Cambridge, CB2 0AH, United Kingdom.
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, WC2R 2LS, United Kingdom.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Prehn
authors.affiliation: Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany 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: Department of Twin Research and Genetic Epidemiology, King's College London, London, WC2R 2LS, United Kingdom Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Gabi
authors.initials: G
authors.lastname: Kastenmüller
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang-Sattler
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, 85764 Neuherberg, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia Novosibirsk State University, 630090 Novosibirsk, Russia.
authors.forename: Yurii S
authors.initials: YS
authors.lastname: Aulchenko
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Janina S
authors.initials: JS
authors.lastname: Ried
mesh_terms: D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D040582:Inheritance Patterns; D055442:Metabolome / Q000235:genetics*; D055432:Metabolomics; D020641:Polymorphism, Single Nucleotide
keywords: KORA; genome-wide association studies; genotypic model; metabolomics; nonadditive models