title: Interrogating causal pathways linking genetic variants, small molecule metabolites, and circulating lipids.
abstract: BACKGROUND
  Emerging technologies based on mass spectrometry or nuclear magnetic resonance enable the monitoring of hundreds of small metabolites from tissues or body fluids. Profiling of metabolites can help elucidate causal pathways linking established genetic variants to known disease risk factors such as blood lipid traits.
  
  
  METHODS
  We applied statistical methodology to dissect causal relationships between single nucleotide polymorphisms, metabolite concentrations, and serum lipid traits, focusing on 95 genetic loci reproducibly associated with the four main serum lipids (total-, low-density lipoprotein-, and high-density lipoprotein- cholesterol and triglycerides). The dataset used included 2,973 individuals from two independent population-based cohorts with data for 151 small molecule metabolites and four main serum lipids. Three statistical approaches, namely conditional analysis, Mendelian randomization, and structural equation modeling, were compared to investigate causal relationship at sets of a single nucleotide polymorphism, a metabolite, and a lipid trait associated with one another.
  
  
  RESULTS
  A subset of three lipid-associated loci (FADS1, GCKR, and LPA) have a statistically significant association with at least one main lipid and one metabolite concentration in our data, defining a total of 38 cross-associated sets of a single nucleotide polymorphism, a metabolite and a lipid trait. Structural equation modeling provided sufficient discrimination to indicate that the association of a single nucleotide polymorphism with a lipid trait was mediated through a metabolite at 15 of the 38 sets, and involving variants at the FADS1 and GCKR loci.
  
  
  CONCLUSIONS
  These data provide a framework for evaluating the causal role of components of the metabolome (or other intermediate factors) in mediating the association between established genetic variants and diseases or traits.
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK ; MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Shin
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg D-85764, Germany.
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Petersen
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg D-85764, Germany ; Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg D-85764, Germany ; German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Wahl
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, London SE1 7EH, UK ; Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, Newfoundland, Canada.
authors.forename: Guangju
authors.initials: G
authors.lastname: Zhai
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg D-85764, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Römisch-Margl
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors.forename: Kerrin S
authors.initials: KS
authors.lastname: Small
authors.affiliation: Institute of Epidemiology I, Helmholtz Zentrum München, Neuherberg D-85764, Germany ; Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg D-85764, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Döring
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, London SE1 7EH, UK ; Respiratory Epidemiology, Occupational Medicine and Public Health, Imperial College London, London SW3 6LR, UK.
authors.forename: Bernet S
authors.initials: BS
authors.lastname: Kato
authors.affiliation: Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg D-85764, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.affiliation: Department of Human Genetics, McGill University, Montreal H3A 1A5, Canada ; Genome Quebec Innovation Centre, McGill University, Montreal H3A 1A5, Canada.
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
authors.affiliation: Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg D-85764, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Prehn
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg D-85764, Germany.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang-Sattler
authors.affiliation: Institute of Epidemiology I, Helmholtz Zentrum München, Neuherberg D-85764, Germany ; Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, München D-81377, Germany ; Klinikum Grosshadern, München D-81377, Germany.
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.affiliation: Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg D-85764, Germany ; Institute of Experimental Genetics, Life and Food Science Center Weihenstephan, Technische Universität München, Freising D-85354, Germany.
authors.forename: Martin Hrabé
authors.initials: MH
authors.lastname: de Angelis
authors.affiliation: Hannover Unified Biobank, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.affiliation: Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg D-85764, Germany ; Institute of Experimental Genetics, Life and Food Science Center Weihenstephan, Technische Universität München, Freising D-85354, Germany.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK ; Willian Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK ; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah 21589, Saudi Arabia.
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg D-85764, Germany ; Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Education City - Qatar Foundation, Doha, Qatar.
authors.forename: Karsten
authors.initials: K
authors.lastname: Suhre
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg D-85764, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK ; Department of Hematology, Long Road, Cambridge CB2 0PT, UK.
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo