Brain-specific epigenetic markers of schizophrenia

Abstract

Epigenetics plays a crucial role in schizophrenia susceptibility. In a previous study, we identified over 4500 differentially methylated sites in prefrontal cortex (PFC) samples from schizophrenia patients. We believe this was the first genome-wide methylation study performed on human brain tissue using the Illumina Infinium HumanMethylation450 Bead Chip. To understand the biological significance of these results, we sought to identify a smaller number of differentially methylated regions (DMRs) of more functional relevance compared with individual differentially methylated sites. Since our schizophrenia whole genome methylation study was performed, another study analysing two separate data sets of post-mortem tissue in the PFC from schizophrenia patients has been published. We analysed all three data sets using the bumphunter function found in the Bioconductor package minfi to identify regions that are consistently differentially methylated across distinct cohorts. We identified seven regions that are consistently differentially methylated in schizophrenia, despite considerable heterogeneity in the methylation profiles of patients with schizophrenia. The regions were near CERS3, DPPA5, PRDM9, DDX43, REC8, LY6G5C and a region on chromosome 10. Of particular interest is PRDM9 which encodes a histone methyltransferase that is essential for meiotic recombination and is known to tag genes for epigenetic transcriptional activation. These seven DMRs are likely to be key epigenetic factors in the aetiology of schizophrenia and normal brain neurodevelopment.

Figure 1

Summary of number of overlapping regions between the three prefrontal cortex data sets. DBCBB, Douglas Bell-Canada Brain Bank; HBSFRC, Human Brain and Spinal Fluid Resource Centre; LBBND, London Brain Bank for Neurodegenerative Disorder.

Figure 2

HBSFRC data set (blue axis), LBBND data set (red axis), DBCBB (green axis) with unadjusted beta values for the control (blue +) and schizophrenia groups (pink x) and the average difference in M-values for each probe; the width of the red highlighted area represents the identified differentially methylated regions, while the height of the region represents the average difference in M-values across the region. The yellow axis represents the known genes downloaded for UCSC browser and the green boxes represent known CpG islands: (a) region near DPPA5; (b) region near DDX43. DBCBB, Douglas Bell-Canada Brain Bank; HBSFRC, Human Brain and Spinal Fluid Resource Centre; LBBND, London Brain Bank for Neurodegenerative Disorder.

Figure 3

HBSFRC data set (blue axis), LBBND data set (red axis), DBCBB (green axis) with unadjusted beta values for the control (blue +) and schizophrenia groups (pink x) and the average difference in M-values for each probe; the width of the red highlighted area represents the identified differentially methylated regions, while the height of the region represents the average difference in M-values across the region. The yellow axis represents the known genes downloaded for UCSC browser and the green boxes represent known CpG islands: (a) region near CERS3; (b) region near PRDM9. DBCBB, Douglas Bell-Canada Brain Bank; HBSFRC, Human Brain and Spinal Fluid Resource Centre; LBBND, London Brain Bank for Neurodegenerative Disorder.