CEEHRC 11th Annual Canadian Conference on Epigenetics

andy Meijer, Kristy Dever, Julia MacIsaac, Gustavo Turecki, Michael Steffen Kobor

Epigenetics has been proposed to reflect the gene-environment interplay. The most studied epigenetic mark in human association studies using peripheral blood is DNA methylation (5mC). Given the tissue-specifity of 5mC, it is unclear whether these associations are reflective of 5mC in the brain, an inaccessible tissue in which DNA hydroxymethylation (5hmC) is also prominently present. Leveraging six-base sequencing, 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 on the level of allele-specific methylation (ASM) and methylation quantitative trait loci (QTLs), and 3) assess whether these genetic variants in both tissues contribute to the genetic risk for psychiatric disorders. By measuring 5mC, 5hmC, and genetic variants throughout the whole genome with six-base sequencing in matched human blood and brain tissue (n = 12; 9 men, 3 women) with ages across the human lifespan, we compared the epigenetic landscape and its genetic context between tissues. 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 hmC 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 (FDR) < 0.05). Furthermore, associations between genetic variants and epigenetic patterns were tissue-specific. Only 26.6% methylation quantitative trait loci (mQTLs) were overlapping between tissues. However, epigenetic similarities of 5mC between tissues were largely driven by genetic variation (Kolmogorov-Smirnov D = 0.88 in blood and 0.46 in brain, p < 2.2*10-16). The genetic variants associated with 5mC, but not 5hmC in the brain specifically, were enriched for genetic risk variants for psychiatric disorders, with SNP heritability up to 0.1 (FDR < 0.05). Understanding 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.