SIX-BASE SEQUENCING IN MATCHED BLOOD AND BRAIN SAMPLES: WIDESPREAD TISSUE-SPECIFIC DNA METHYLATION AND HYDROXYMETHYLATION PROFILES

Epigenetics has been proposed to reflect the gene-environment interplay. The most studied epigenetic mark in human studies is DNA methylation (5mC). Given its tissue-specificity, it is unclear whether findings from the periphery are reflective of the brain, where DNA hydroxymethylation (5hmC) is also prominently present. We aim to 1) compare 5mC and 5hmC levels between blood and brain throughout the whole genome; 2) assess the genetic effects on both 5mC and 5hmC in blood and brain, and 3) assess whether these genetic variants in both tissues contribute to the genetic risk for psychiatric disorders. To compare epigenetic landscapes between tissues, six-base sequencing was performed on twelve (9 men; 3 women) matched Brodmann Area 10 and peripheral blood samples (mean age = 64.52 years, range = 41-87 years) from the Quebec Suicide Brain Bank with biomodal duet multiomics solution +modC (Cambridge, UK). We showed that levels of modified cytosines in CpG context were higher in brain than in blood (75.94% versus 57.41%, p = 4.09*10^-16), and 5hmC modifications were mostly present in regulatory genomic regions. A small proportion of CpG sites – which was lower than previously described – showed blood-brain correlation (2.44% and 0.08% of 5mC and 5hmC, respectively; false discovery rate < 0.05). Integrating these findings with genetic data will help us understand the similarities and differences of epigenetic patterns across tissues will facilitate the study of brain-related traits in accessible non-invasive peripheral samples in a biological meaningful way.