Peripheral blood gene expression profiles linked to monoamine metabolite levels in cerebrospinal fluid.

J J Luykx,P Bruins,E Lentjes,P Borgdorff,R S Kahn,E Strengman,R A Ophoff,S Horvath,L M Olde Loohuis,S De Jong,E P A Van Dongen,M Neeleman,S C Bakker

doi:10.1038/tp.2016.245

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.

Highlights

Gene expression profiling analysis constitutes a powerful tool to increase our understanding of neurobiological mechanisms influencing health and disease, including psychiatric disorders such as schizophrenia,[1] major depressive disorder,[2,3] bipolar disorder[4] and 22q11 deletion syndrome-associated psychosis.[5]Integrating transcriptomics with metabolomics approaches may signal neurobiological mechanisms that regulate the metabolome, as demonstrated for the mouse liver.[6]
It is currently unknown to what degree gene expression levels in blood may be informative for metabolic processes relevant to the central nervous system (CNS) and whether peripheral gene expression levels are linked to CNS metabolism
The primary metabolites of the monoamines—5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 5-medroxy-4hydroxyphenylglycol (MHPG)—are implicated in physiological CNS processes and neurobehavioral traits, most notably mood disorders[8,9] and Brunner syndrome.[10]

Summary

Introduction

Gene expression profiling analysis constitutes a powerful tool to increase our understanding of neurobiological mechanisms influencing health and disease, including psychiatric disorders such as schizophrenia,[1] major depressive disorder,[2,3] bipolar disorder[4] and 22q11 deletion syndrome-associated psychosis.[5]Integrating transcriptomics with metabolomics approaches may signal neurobiological mechanisms that regulate the metabolome, as demonstrated for the mouse liver.[6]. Gene expression profiling analysis constitutes a powerful tool to increase our understanding of neurobiological mechanisms influencing health and disease, including psychiatric disorders such as schizophrenia,[1] major depressive disorder,[2,3] bipolar disorder[4] and 22q11 deletion syndrome-associated psychosis.[5]. Studies comparing transcripts in blood with postmortem brain tissue were recently reviewed,[7] no investigations relating cerebrospinal fluid (CSF) to peripheral gene expression have been published. The primary metabolites of the monoamines—5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 5-medroxy-4hydroxyphenylglycol (MHPG)—are implicated in physiological CNS processes (ranging from cognitive functioning to reproduction) and neurobehavioral traits, most notably mood disorders[8,9] and Brunner syndrome.[10] Monoamine metabolites (MMs) can be measured in CSF.[11] Evidence from genome-wide linkage and association studies[11,12] attests to the genetic underpinnings of monoamine turnover in CSF

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Conclusion