Interindividual methylomic variation across blood, cortex, and cerebellum: implications for epigenetic studies of neurological and neuropsychiatric phenotypes

TLDR

Epigenetic processes are tissue‑specific, and it is unclear whether accessible tissues like whole blood can capture interindividual epigenomic variation in brain regions relevant to neurological disorders. The study aimed to assess how well methylomic variation in blood predicts interindividual variation in the brain. DNA methylation was quantified in matched whole‑blood and four brain region samples from 122 individuals, and co‑variation between tissues was examined to evaluate blood’s predictive value for brain methylation. Results showed that blood variation poorly predicts brain variation overall, with stronger but still limited correlation in cortical regions versus cerebellum; a subset of probes exhibited cross‑tissue correlation likely driven by genetics, indicating that blood‑based EWAS will provide limited insight into brain pathology yet may still identify disease biomarkers, and a searchable database is available.

Abstract

Given the tissue-specific nature of epigenetic processes, the assessment of disease-relevant tissue is an important consideration for epigenome-wide association studies (EWAS). Little is known about whether easily accessible tissues, such as whole blood, can be used to address questions about interindividual epigenomic variation in inaccessible tissues, such as the brain. We quantified DNA methylation in matched DNA samples isolated from whole blood and 4 brain regions (prefrontal cortex, entorhinal cortex, superior temporal gyrus, and cerebellum) from 122 individuals. We explored co-variation between tissues and the extent to which methylomic variation in blood is predictive of interindividual variation identified in the brain. For the majority of DNA methylation sites, interindividual variation in whole blood is not a strong predictor of interindividual variation in the brain, although the relationship with cortical regions is stronger than with the cerebellum. Variation at a subset of probes is strongly correlated across tissues, even in instances when the actual level of DNA methylation is significantly different between them. A substantial proportion of this co-variation, however, is likely to result from genetic influences. Our data suggest that for the majority of the genome, a blood-based EWAS for disorders where brain is presumed to be the primary tissue of interest will give limited information relating to underlying pathological processes. These results do not, however, discount the utility of using a blood-based EWAS to identify biomarkers of disease phenotypes manifest in the brain. We have generated a searchable database for the interpretation of data from blood-based EWAS analyses (http://epigenetics.essex.ac.uk/bloodbrain/).