On the outside, looking in: A review and evaluation of the comparability of blood and brain “‐omes”

Abstract

In this article, we review studies detailing the correspondence between peripheral blood and brain tissue across various domains of high-throughput -omic analysis in order to provide a context for evaluating blood-based biomarker studies. Specifically, we reviewed seven studies comparing patterns of DNA methylation (i.e., an aspect of the epigenome), eight articles comparing patterns of gene expression (i.e., the transcriptome), and three articles comparing patterns of protein expression (i.e., the proteome). Our review of the epigenomic literature suggests that CpG-island methylation levels are generally highly correlated (r ¼ 0.90) between blood and brain. Our review of transcriptomic studies suggests that between 35% and 80% of known transcripts are present in both brain and blood tissue samples; estimates of cross-tissue correlation in expression levels were found to range from 0.25 to 0.64, with stronger correlations observed among particular subsets of genes. Relative to the epigenome and transcriptome, the proteome has not been as fully compared between brain and blood samples, highlighting an important area for future work as whole-proteome profiling methods mature. Beyond reviewing the relevant studies, we discuss some of the assumptions, methodological issues, and gaps in knowledge that should be addressed in order to better understand how the multiple ''-omes'' of the brain are reflected in the peripheral blood. A better understanding of these relationships is a critical precursor to the validation of biomarkers for brain disorders. Ó 2013 Wiley Periodicals, Inc.Key words: blood; brain; epigenome; gene expression; genome; methylation; neuropsychiatry; proteome; transcriptome INTRODUCTIONTechnological advances in molecular biology over the last two decades have fundamentally altered our approach to studying brain disorders. The ''throughput'' of many molecular-profiling techniques, which had heretofore been a major bottleneck to discovery, has increased exponentially. This, in turn, has initiated a notable trend in the field away from hypothesis-testing of candidate genes, transcripts, and proteins, and toward hypothesis-generation through the simultaneous evaluation of all members of a particular molecular species (i.e., an ''-ome''). As a consequence, the number of -omes entering the scientific vernacular has also increased rapidly to include the genome (all DNA sequence variations), epigenome (all chemical modifications to the DNA and histone proteins), transcriptome (all expressed RNA transcripts), and proteome (all expressed proteins), among others.Given the demonstrable heritability of many neuropsychiatric disorders [Glatt et al., 2010], much research has been dedicated to identifying the genomic variations underlying their susceptibility. These genomic studies have been predicated on the fundamental and largely true assumption that the genome is equivalent in sequence and structure in all cells and tissues of the same organism. This tenet allows for the standard practice of examining DNA sequen...

DNA methylation analysis of Homeobox genes implicatesHOXB7hypomethylation as risk factor for neural tube defects

“…Concordant DNA methylation profiles in brain and blood samples from the same individuals suggest that blood might hold promise as surrogate for brain tissue to detect DNA methylation. [28][29][30] Genome-wide methylation arrays revealed similar methylation patterns for the HOX genes in breast cancers and white blood cells, which suggests that methylation is more likely to be a normal developmental and tissue-specific process that does not directly relate to the malignant mechanism. 31 Interestingly, functional in silico analysis using the MENT database showed no correlation with gene expression in normal brain and blood tissues for the methylation of 2 HOXB7 promoter CpGs but there is evidence that lower HOXB7 methylation values in brain tightly regulate Figure 3.…”

Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response

“…Gene expression (mRNA levels) and protein level measures are useful complementary data to genetic and epigenetic information, since several levels of regulation occur after gene translation (i.e., post-translational modifications involving addition of functional groups or other proteins/peptides, structural changes, catabolic processes). Blood cells represent an easily available sample for gene expression studies and they share between 35 and 80% of the transcriptome with the brain (Tylee et al 2013). A particular type of ribonucleic acid (RNA) known as microRNA (miRNA) received attention recently because miRNAs function as modulators of the degradation and translation of messenger RNA (mRNA), thus they represent a fundamental regulatory step in the process leading to protein production.…”

Methylome analysis for spina bifida shows SOX18 hypomethylation as risk factor with evidence for a complex (epi)genetic interplay to affect neural tube development

“…The father is carrier of the BMP4 deletion methylation of the same gene set would be observed in brain or spinal cord tissue of MMC patients. But concordant methylation alterations in brain and blood suggest that blood methylation might be representative for brain methylation [38][39][40][41][42]. Hannon et al generated an online tool which allows to investigate the correlation of DNA methylation of blood and four brain regions for all probes present on the HM450k [43].…”