Correspondence of DNA Methylation Between Blood and Brain Tissue and Its Application to Schizophrenia Research

Abstract

Given the difficulty of procuring human brain tissue, a key question in molecular psychiatry concerns the extent to which epigenetic signatures measured in more accessible tissues such as blood can serve as a surrogate marker for the brain. Here, we aimed (1) to investigate the blood-brain correspondence of DNA methylation using a within-subject design and (2) to identify changes in DNA methylation of brain-related biological pathways in schizophrenia.We obtained paired blood and temporal lobe biopsy samples simultaneously from 12 epilepsy patients during neurosurgical treatment. Using the Infinium 450K methylation array we calculated similarity of blood and brain DNA methylation for each individual separately. We applied our findings by performing gene set enrichment analyses (GSEA) of peripheral blood DNA methylation data (Infinium 27K) of 111 schizophrenia patients and 122 healthy controls and included only Cytosine-phosphate-Guanine (CpG) sites that were significantly correlated across tissues.Only 7.9% of CpG sites showed a statistically significant, large correlation between blood and brain tissue, a proportion that although small was significantly greater than predicted by chance. GSEA analysis of schizophrenia data revealed altered methylation profiles in pathways related to precursor metabolites and signaling peptides.Our findings indicate that most DNA methylation markers in peripheral blood do not reliably predict brain DNA methylation status. However, a subset of peripheral data may proxy methylation status of brain tissue. Restricting the analysis to these markers can identify meaningful epigenetic differences in schizophrenia and potentially other brain disorders.

Sex and Diagnosis-Specific Associations Between DNA Methylation of the Oxytocin Receptor Gene With Emotion Processing and Temporal-Limbic and Prefrontal Brain Volumes in Psychotic Disorders

“…Nevertheless, findings from our previous studies focusing on peripheral OT levels and social cognition, which have used the present assay methodologies (7), have been replicated by researchers using different assay methods (9). Fifth, we focused on methylation levels of a single CpG site in the promoter region of OXTR and assayed peripherally derived DNA from blood which are imperfect markers of brain DNA methylation (86). Although we do not know the exact association between blood and brain methylation at CpG site -934, a number of studies to date reflect the utility of this peripheral assay in predicting brain endophenotypes related to social cognition (34, 35).…”

The role of DNA methylation in the pathophysiology and treatment of bipolar disorder

“…However, the studies on this topic are still controversial, and some findings indicate that most DNA methylation markers in peripheral blood do not reliably predict brain DNA methylation status (Walton et al, 2016). Only a specific subset of peripheral data was shown to proxy methylation status of brain tissue, which suggests that studies on peripheral methylation should ideally restrict their analysis to these markers (Walton et al, 2016).…”

Prenatal Diet and Childhood ADHD: Exploring the Potential Role of IGF2 Methylation

“…Third, although the use of peripheral tissue samples hold potential for the identification of exposure/risk biomarkers, the extent to which findings may reflect methylation changes in the brain is unclear. In fact, a recent study [26] found that most DNA methylation markers in peripheral blood do not reliably predict brain DNA methylation status, making inferences on brain-relevant processes difficult. As such, it will be important to establish to what extent peripheral levels of IGF2 methylation relate to in vivo structural/functional neural markers of ADHD.…”