Blood-Based miRNA Biomarkers as Correlates of Brain-Based miRNA Expression

Abstract

The use of easily accessible peripheral samples, such as blood or saliva, to investigate neurological and neuropsychiatric disorders is well-established in genetic and epigenetic research, but the pathological implications of such biomarkers are not easily discerned. To better understand the relationship between peripheral blood- and brain-based epigenetic activity, we conducted a pilot study on captive baboons (Papio hamadryas) to investigate correlations between miRNA expression in peripheral blood mononuclear cells (PBMCs) and 14 different cortical and subcortical brain regions, represented by two study groups comprised of 4 and 6 animals. Using next-generation sequencing, we identified 362 miRNAs expressed at ≥ 10 read counts in 80% or more of the brain samples analyzed. Nominally significant pairwise correlations (one-sided P < 0.05) between peripheral blood and mean brain expression levels of individual miRNAs were observed for 39 and 44 miRNAs in each group. When miRNA expression levels were averaged for tissue type across animals within the groups, Spearman’s rank correlations between PBMCs and the brain regions are all highly significant (rs = 0.47–0.57; P < 2.2 × 10–16), although pairwise correlations among the brain regions are markedly stronger (rs = 0.86–0.99). Principal component analysis revealed differentiation in miRNA expression between peripheral blood and the brain regions for the first component (accounting for ∼75% of variance). Linear mixed effects modeling attributed most of the variance in expression to differences between miRNAs (>70%), with non-significant 7.5% and 13.1% assigned to differences between blood and brain-based samples in the two study groups. Hierarchical UPGMA clustering revealed a major co-expression branch in both study groups, comprised of miRNAs globally upregulated in blood relative to the brain samples, exhibiting an enrichment of miRNAs expressed in immune cells (CD14+, CD15+, CD19+, CD3+, and CD56 + leukocytes) among the top blood-brain correlates, with the gene MYC, encoding a master transcription factor that regulates angiogenesis and neural stem cell activation, representing the most prevalent miRNA target. Although some differentiation was observed between tissue types, these preliminary findings reveal wider correlated patterns between blood- and brain-expressed miRNAs, suggesting the potential utility of blood-based miRNA profiling for investigating by proxy certain miRNA activity in the brain, with implications for neuroinflammatory and c-Myc-mediated processes.

Loss of schizophrenia-related miR-501-3p in mice impairs sociability and memory by enhancing mGluR5-mediated glutamatergic transmission

“…Schizophrenia is a complex polygenetic disease and is characterized by extreme heterogeneity. miRNAs perform their regulatory function by binding to the 3′UTRs of many targets, and as altered miRNA profiles have been implicated in schizophrenia (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), the functional contribution of molecular networks and interactions among many targets of individual miRNAs to the pathogenesis of schizophrenia is largely unknown. In this study, we used SDC MZ twins to screen DE-miRNAs associated with disease susceptibility of MZ twins.…”

“…The functional importance of miRNA regulatory networks in neurodevelopment and brain physiology has been widely studied (6,7), and many studies have shown that these networks play essential roles in schizophrenia (3), providing for implication of miRNAs in the etiology and pathophysiology of schizophrenia. Many studies have reported that hundreds of miRNAs are dysregulated in postmortem brains or peripheral blood of people with schizophrenia (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18); however, only a few miRNAs have been validated in rodent models, and many of their functions are still not known. Although miRNA profiles in postmortem brain remain to be determined, it is reasonable that change of miRNA expression extending beyond the brain could provide useful peripheral biomarkers for schizophrenia.…”

“…Although miRNA profiles in postmortem brain remain to be determined, it is reasonable that change of miRNA expression extending beyond the brain could provide useful peripheral biomarkers for schizophrenia. Recent findings that substantial correlation between blood and brains in miRNA expression (14) supported feasibility to probe the miRNAs related to neural function in the peripheral blood transcriptome. Given that many miRNAs target synaptic proteins or signaling proteins regulating synapses (6,7,(18)(19)(20), the implication of synaptic plasticity in cognition and the genetic association of miRNAs (such as miR-137) with schizophrenia raises the possibility that miRNAs contribute to the pathogenesis of schizophrenia through regulation of synaptic plasticity.…”

Clinical Utility of Fluid Biomarker in Depressive Disorder

“…Other studies have demonstrated that, in some cases, measures in blood are very similar to those at the level of the central nervous system [ 54 ]. As an example, blood miRNA levels were shown to largely correlate with brain expression [ 55 ]. Indeed, miRNA circulating levels are a promising field of investigation [ 56 - 60 ].…”

miRNAs and isomiRs: Serum-Based Biomarkers for the Development of Intellectual Disability and Autism Spectrum Disorder in Tuberous Sclerosis Complex

“…Other mechanisms of release include active secretion through microvesicles [ 35 , 36 , 37 ], such as exosomes or active release without microvesicles through RNA-binding protein dependent pathways [ 38 ]. Furthermore, a recent study has reported correlated patterns between blood-and brain-expressed miRNAs, indicating a potential use of blood-based miRNA profiling for the investigation of miRNA activity in the brain [ 39 ]. Nevertheless, further investigation is required on the correlation between miRNA dysregulation in the brain and their expression in serum.…”