title: Integration of Genome-Wide SNP Data and Gene-Expression Profiles Reveals Six Novel Loci and Regulatory Mechanisms for Amino Acids and Acylcarnitines in Whole Blood.
abstract: Profiling amino acids and acylcarnitines in whole blood spots is a powerful tool in the laboratory diagnosis of several inborn errors of metabolism. Emerging data suggests that altered blood levels of amino acids and acylcarnitines are also associated with common metabolic diseases in adults. Thus, the identification of common genetic determinants for blood metabolites might shed light on pathways contributing to human physiology and common diseases. We applied a targeted mass-spectrometry-based method to analyze whole blood concentrations of 96 amino acids, acylcarnitines and pathway associated metabolite ratios in a Central European cohort of 2,107 adults and performed genome-wide association (GWA) to identify genetic modifiers of metabolite concentrations. We discovered and replicated six novel loci associated with blood levels of total acylcarnitine, arginine (both on chromosome 6; rs12210538, rs17657775), propionylcarnitine (chromosome 10; rs12779637), 2-hydroxyisovalerylcarnitine (chromosome 21; rs1571700), stearoylcarnitine (chromosome 1; rs3811444), and aspartic acid traits (chromosome 8; rs750472). Based on an integrative analysis of expression quantitative trait loci in blood mononuclear cells and correlations between gene expressions and metabolite levels, we provide evidence for putative causative genes: SLC22A16 for total acylcarnitines, ARG1 for arginine, HLCS for 2-hydroxyisovalerylcarnitine, JAM3 for stearoylcarnitine via a trans-effect at chromosome 1, and PPP1R16A for aspartic acid traits. Further, we report replication and provide additional functional evidence for ten loci that have previously been published for metabolites measured in plasma, serum or urine. In conclusion, our integrative analysis of SNP, gene-expression and metabolite data points to novel genetic factors that may be involved in the regulation of human metabolism. At several loci, we provide evidence for metabolite regulation via gene-expression and observed overlaps with GWAS loci for common diseases. These results form a strong rationale for subsequent functional and disease-related studies.
authors.affiliation: LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Burkhardt
authors.affiliation: LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany; Department for Cell Therapy, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Kirsten
authors.affiliation: LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Heart Center Leipzig, Leipzig, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Beutner
authors.affiliation: LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Institute for Laboratory Medicine, Ludwig-Maximilians University Munich, Munich, Germany.
authors.forename: Lesca M
authors.initials: LM
authors.lastname: Holdt
authors.affiliation: LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
authors.forename: Arnd
authors.initials: A
authors.lastname: Gross
authors.affiliation: LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Heart Center Leipzig, Leipzig, Germany.
authors.forename: Andrej
authors.initials: A
authors.lastname: Teren
authors.affiliation: Medical Department, Clinic for Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Tönjes
authors.affiliation: LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Susen
authors.initials: S
authors.lastname: Becker
authors.affiliation: LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig, Germany.
authors.forename: Knut
authors.initials: K
authors.lastname: Krohn
authors.affiliation: Integrated Research and Treatment Center Adiposity Diseases, University of Leipzig, Leipzig Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
authors.affiliation: Medical Department, Clinic for Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany; Integrated Research and Treatment Center Adiposity Diseases, University of Leipzig, Leipzig Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stumvoll
authors.affiliation: LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Institute for Laboratory Medicine, Ludwig-Maximilians University Munich, Munich, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Teupser
authors.affiliation: LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Thiery
authors.affiliation: LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Ceglarek
authors.affiliation: LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Scholz
mesh_terms: D000596:Amino Acids / Q000097:blood*; D002331:Carnitine / Q000031:analogs & derivatives* / Q000097:blood; D015331:Cohort Studies; D004194:Disease / Q000235:genetics; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: D000596:Amino Acids; C116917:acylcarnitine; D002331:Carnitine