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.

Figure 1

Depicted are the five genes within modules that were significantly associated with monoamine metabolites and that have been implicated in psychiatric illness or monoamine metabolism. (a) Correlation between the 5-HIAA/HVA concentration ratio in CSF and expression levels of the gene HTR2A. (b) Correlation between the 5-HIAA/HVA concentration ratio in CSF and expression levels of the gene GNAI3. (c) Correlation between the 5-HIAA/HVA concentration ratio in CSF and expression levels of the gene GSK3B. (d) Correlation between the MHPG/HVA concentration ratio in CSF and expression levels of the gene TCF4. (e) Correlation between the 5-HIAA/HVA concentration ratio in CSF and expression levels of the gene COMT. Each dot represents one healthy subject. Summary statistics are shown in the figures. COMT, catechol-O-methyltransferase; CSF, cerebrospinal fluid.