title: The Human Blood Metabolome-Transcriptome Interface.
abstract: Biological systems consist of multiple organizational levels all densely interacting with each other to ensure function and flexibility of the system. Simultaneous analysis of cross-sectional multi-omics data from large population studies is a powerful tool to comprehensively characterize the underlying molecular mechanisms on a physiological scale. In this study, we systematically analyzed the relationship between fasting serum metabolomics and whole blood transcriptomics data from 712 individuals of the German KORA F4 cohort. Correlation-based analysis identified 1,109 significant associations between 522 transcripts and 114 metabolites summarized in an integrated network, the 'human blood metabolome-transcriptome interface' (BMTI). Bidirectional causality analysis using Mendelian randomization did not yield any statistically significant causal associations between transcripts and metabolites. A knowledge-based interpretation and integration with a genome-scale human metabolic reconstruction revealed systematic signatures of signaling, transport and metabolic processes, i.e. metabolic reactions mainly belonging to lipid, energy and amino acid metabolism. Moreover, the construction of a network based on functional categories illustrated the cross-talk between the biological layers at a pathway level. Using a transcription factor binding site enrichment analysis, this pathway cross-talk was further confirmed at a regulatory level. Finally, we demonstrated how the constructed networks can be used to gain novel insights into molecular mechanisms associated to intermediate clinical traits. Overall, our results demonstrate the utility of a multi-omics integrative approach to understand the molecular mechanisms underlying both normal physiology and disease.
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Bartel
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Krumsiek
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Neuherberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Schramm
authors.affiliation: Institute of Experimental Genetics, Genome Analysis Center Helmholtz Zentrum München, Neuherberg, Germany; Faculty of Experimental Genetics, Technische Universität München, Freising-Weihenstephan, Germany; German Center for Cardiovascular Disease Research (DZHK e.V.), partner-site Munich, Munich, Germany.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), partner-site Düsseldorf, Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Herder
authors.affiliation: Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), partner-site Düsseldorf, Düsseldorf, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Carstensen
authors.affiliation: German Center for Cardiovascular Disease Research (DZHK e.V.), partner-site Munich, Munich, Germany; Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany; German Center for Cardiovascular Disease Research (DZHK e.V.), partner-site Munich, Munich, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.affiliation: Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rathmann
authors.affiliation: Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), partner-site Düsseldorf, Düsseldorf, Germany; Department of Endocrinology and Diabetology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Roden
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany; Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Qatar Foundation, Doha, Qatar.
authors.forename: Karsten
authors.initials: K
authors.lastname: Suhre
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Gabi
authors.initials: G
authors.lastname: Kastenmüller
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Neuherberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany; Department of Mathematics, Technische Universität München, Garching, Germany.
authors.forename: Fabian J
authors.initials: FJ
authors.lastname: Theis
mesh_terms: D000368:Aged; D005215:Fasting / Q000097:blood*; D005260:Female; D053263:Gene Regulatory Networks; D015894:Genome, Human; D006801:Humans; D008297:Male; D055442:Metabolome; D008875:Middle Aged; D059467:Transcriptome