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. 2017 Jan 3;7(1):e989.
doi: 10.1038/tp.2016.249.

Methylomic Profiling of Cortex Samples From Completed Suicide Cases Implicates a Role for PSORS1C3 in Major Depression and Suicide

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Free PMC article

Methylomic Profiling of Cortex Samples From Completed Suicide Cases Implicates a Role for PSORS1C3 in Major Depression and Suicide

T M Murphy et al. Transl Psychiatry. .
Free PMC article

Abstract

Major depressive disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for suicide. The molecular pathology of suicidal depression remains poorly understood, although it has been hypothesised that regulatory genomic processes are involved in the pathology of both MDD and suicidality. In this study, genome-wide patterns of DNA methylation were assessed in depressed suicide completers (n=20) and compared with non-psychiatric, sudden-death controls (n=20) using tissue from two cortical brain regions (Brodmann Area 11 (BA11) and Brodmann Area 25 (BA25)). Analyses focused on identifying differentially methylated regions (DMRs) associated with suicidal depression and epigenetic variation were explored in the context of polygenic risk scores for major depression and suicide. Weighted gene co-methylation network analysis was used to identify modules of co-methylated loci associated with depressed suicide completers and polygenic burden for MDD and suicide attempt. We identified a DMR upstream of the PSORS1C3 gene, subsequently validated using bisulfite pyrosequencing and replicated in a second set of suicide samples, which is characterised by significant hypomethylation in both cortical brain regions in MDD suicide cases. We also identified discrete modules of co-methylated loci associated with polygenic risk burden for suicide attempt, but not major depression. Suicide-associated co-methylation modules were enriched among gene networks implicating biological processes relevant to depression and suicidality, including nervous system development and mitochondria function. Our data suggest that there are coordinated changes in DNA methylation associated with suicide that may offer novel insights into the molecular pathology associated with depressed suicide completers.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
DNA methylation cross-tissue correlations. Correlation of effect sizes (mean adjusted beta difference) across the two brain regions of matched individuals at (a) nominally significant (P<0.05) BA25-associated DMPs and (b) nominally significant (P<0.05) BA11-associated DMPs. The mean adjusted beta differences at these loci were significantly positively correlated between brain regions (P<2.2 × 10−16). In addition, nominally significant DMPs exhibiting larger absolute beta differences (absolute Δβ⩾0.05; BA11 (n=181); BA25 (n=282) showed strong positive correlations when compared across the two brain regions (Pearson’s r=0.8, Pearson’s r=0.87, respectively, shown in red). BA11, Brodmann Area 11; BA25, Brodmann Area 25; DMP, differentially methylated position.
Figure 2
Figure 2
DNA hypomethylation of DMR upstream of the PSORS1C3 non-coding gene. (a) Idiogram of chromosome 6 with genomic coordinates of DMR illustrated. The DMR—spanning 13 CpG sites—overlaps a CpG island (shown in blue). (b) PSORS1C3-associated DMR is hypomethylated across all 13 CpG sites in MDD suicide cases compared with controls in both brain regions. (c) Consistent with our findings, we observed DNA hypomethylation across all CpG sites present in the DMR in suicide cases compared with non-suicide controls in an independent suicide brain replication cohort. Two CpG sites (*) within the DMR were significantly differentially methylated between cases and controls (cg26818629 (P=0.03); cg26668675 (P=0.04)). DMR, differentially methylated region; MDD, major depressive disorder.
Figure 3
Figure 3
Technical validation of PSORS1C3-associated DMR using bisulfite pyrosequencing. Correlation of the mean DNA methylation values (at 10 CpG sites) obtained from the 450 k array (y axis) and bisulfite pyrosequencing (x axis) for samples in the brain region (a) BA11 (Pearson’s r=0.97; P-value<2.2 × 10−16) and (b) BA25 (Pearson’s r=0.97; P-value=1.07 × 10−13). BA11, Brodmann Area 11; BA25, Brodmann Area 25; DMR, differentially methylated region.
Figure 4
Figure 4
Modules of co-methylated loci are associated with both MDD suicide completers and SA PRS in brain region BA25. (a) Heatmap representing correlations between ME of diagnosis-associated modules and phenotype traits (diagnosis, MDD PRS and SA PRS). Each row represents a BA25 module, which is labelled with an arbitrary colour. Dark red indicates strong positive correlation, dark blue indicates strong negative correlation and white indicates no correlation (see colour scale bar). Uncorrected P-values are given in parentheses. The darkorange2 (P=0.02) and white (P=0.04) modules are also significantly associated with SA PRS in the BA25 brain region. (b) Boxplots and scatterplots of ME against diagnosis (control versus MDD suicide) and SA PRS, respectively. (c) Co-methylation networks between hub loci (module membership⩾0.8) in the white module, where larger circles indicate higher connectivity. Dark blue colour indicates a smaller P-value obtained from the probewise regression analysis examining the relationship between probes/genes and diagnosis (MDD suicide cases compared with controls), whereas white indicates a larger P-value. (d) Co-methylation networks between hub loci in the darkorange2 module, where larger circles indicate higher connectivity. Dark orange colour indicates a smaller P-value obtained from the probewise regression analysis examining the relationship between probes/genes and diagnosis (MDD suicide cases compared with controls), whereas white indicates a larger P-value. BA25, Brodmann Area 25; MDD, major depressive disorder; ME, module eigengene; PRS, polygenic risk score; SA, suicide attempt.

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