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Blood-based miRNA biomarkers as correlates of brain-based miRNA expression

ABSTRACT: 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 across animals within the groups, pairwise correlations between PBMCs and individual brain regions are all highly significant (P<2.2x10^-16), although correlations between brain regions are markedly stronger (rs=0.86-0.99) than those between blood and brain (rs=0.47-0.57). 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 two major co-expression branches that are evident in both groups, with one comprised of miRNAs hyper-expressed 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. In the other major branch, hypo-expression in the blood samples was observed, with enrichment for miRNAs associated with Alzheimer’s Disease among its top correlates. Although some differentiation was observed between tissue types, these preliminary findings reveal wider correlated patterns between blood- and brain-expressed miRNAs, suggesting the utility of blood-based miRNA profiling for investigating by proxy the epigenetic underpinnings of neurological and neuroinflammatory processes in the brain.

ORGANISM(S): Papio hamadryas

PROVIDER: GSE190675 | GEO | 2021/12/14

REPOSITORIES: GEO

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Project description:Neuroepigenetics considers genetic sequences and the interplay with environmental influences to elucidate vulnerability risk for various neurological and psychiatric disorders. However, evaluating DNA methylation of brain tissue is challenging owing to the issue of tissue specificity. Consequently, peripheral surrogate tissues were used, resulting in limited progress compared with other epigenetic studies, such as cancer research. Therefore, we developed databases to establish correlations between the brain and peripheral tissues in the same individuals. Four tissues, resected brain tissue, blood, saliva, and buccal mucosa (buccal), were collected from 19 patients (aged 13–73 years) who underwent neurosurgery. Moreover, their genome-wide DNA methylation was assessed using the Infinium HumanMethylationEPIC BeadChip arrays to determine the cross-tissue correlation of each combination. These correlation analyses were conducted with all methylation sites and with variable CpGs, and with when these were adjusted for cellular proportions. For the averaged data for each CpG across individuals, the saliva–brain correlation (r = 0.90) was higher than that for blood–brain (r = 0.87) and buccal–brain (r = 0.88) comparisons. Among individual CpGs, blood had the highest proportion of CpGs correlated to the brain at nominally significant levels (19.0%), followed by saliva (14.4%) and buccal (9.8%). These results were similar to the previous IMAGE-CpG results; however, the correlation analysis between the correlation coefficients of the datasets revealed a relatively low degree of correlation (brain vs. blood: r = 0.27, saliva; r = 0.18, and buccal; r = 0.24). To the best of our knowledge, this is the fourth study in the literature initiating the development of databases for correlations between the brain and peripheral tissues in the same individuals. We present the first database developed from an Asian population, specifically Japanese samples (AMAZE-CpG), which would contribute to interpreting individual epigenetic study results from various Asian populations.

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Blood-based miRNA biomarkers as correlates of brain-based miRNA expression

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