title: Peripheral blood gene expression profiles linked to monoamine metabolite levels in cerebrospinal fluid.
abstract: The blood-brain barrier separates circulating blood from the central nervous system (CNS). The scope of this barrier is not fully understood which limits our ability to relate biological measurements from peripheral to central phenotypes. For example, it is unknown to what extent gene expression levels in peripheral blood are reflective of CNS metabolism. In this study, we examine links between central monoamine metabolite levels and whole-blood gene expression to better understand the connection between peripheral systems and the CNS. To that end, we correlated the prime monoamine metabolites in cerebrospinal fluid (CSF) with whole-genome gene expression microarray data from blood (N=240 human subjects). We additionally applied gene-enrichment analysis and weighted gene co-expression network analyses (WGCNA) to identify modules of co-expressed genes in blood that may be involved with monoamine metabolite levels in CSF. Transcript levels of two genes were significantly associated with CSF serotonin metabolite levels after Bonferroni correction for multiple testing: THAP7 (P=2.8 × 10-8, β=0.08) and DDX6 (P=2.9 × 10-7, β=0.07). Differentially expressed genes were significantly enriched for genes expressed in the brain tissue (P=6.0 × 10-52). WGCNA revealed significant correlations between serotonin metabolism and hub genes with known functions in serotonin metabolism, for example, HTR2A and COMT. We conclude that gene expression levels in whole blood are associated with monoamine metabolite levels in the human CSF. Our results, including the strong enrichment of brain-expressed genes, illustrate that gene expression profiles in peripheral blood can be relevant for quantitative metabolic phenotypes in the CNS.
authors.affiliation: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Translational Neuroscience Human Neurogenetics Unit, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Psychiatry, ZNA Hospitals, Antwerp, Belgium.
authors.forename: J J
authors.initials: JJ
authors.lastname: Luykx
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Olde Loohuis
authors.affiliation: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Neeleman
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Strengman
authors.affiliation: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: S C
authors.initials: SC
authors.lastname: Bakker
authors.affiliation: Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Lentjes
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Management, Diakonessenhuis Hospital, Utrecht, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Borgdorff
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Management, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: E P A
authors.initials: EP
authors.lastname: van Dongen
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Management, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Bruins
authors.affiliation: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: R S
authors.initials: RS
authors.lastname: Kahn
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.|Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Horvath
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: de Jong
authors.affiliation: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.|Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA.|Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Ophoff
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015306:Biogenic Monoamines / Q000134:cerebrospinal fluid*; D001921:Brain / Q000378:metabolism; D058068:Endophenotypes; D005260:Female; D020869:Gene Expression Profiling; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000134:cerebrospinal fluid; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000134:cerebrospinal fluid; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values; D012701:Serotonin / Q000134:cerebrospinal fluid / Q000235:genetics; D055815:Young Adult
chemical_list: D015306:Biogenic Monoamines; D012333:RNA, Messenger; D012701:Serotonin; D008734:Methoxyhydroxyphenylglycol; D006897:Hydroxyindoleacetic Acid; D006719:Homovanillic Acid