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Articles   |    
Genome-Wide Methylation Changes in the Brains of Suicide Completers
Benoit Labonté, M.Sc.; Matt Suderman, Ph.D.; Gilles Maussion, Ph.D.; Juan Pablo Lopez, B.Sc.; Luis Navarro-Sánchez, M.Sc.; Volodymyr Yerko, Ph.D.; Naguib Mechawar, Ph.D.; Moshe Szyf, Ph.D.; Michael J. Meaney, Ph.D.; Gustavo Turecki, M.D., Ph.D.
Am J Psychiatry 2013;170:511-520. doi:10.1176/appi.ajp.2012.12050627
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Dr. Mechawar has received speaking fees from Eli Lilly Canada. The other authors report no financial relationships with commercial interests.

Supported by grant MOP84291 from the Canadian Institute of Health Research (CIHR), by a NARSAD Independent Investigator Award to Dr. Turecki, and by support to the Brain Bank from the Réseau Québécois de Recherche en Santé. Dr. Turecki is a national researcher of the Fonds de Recherche du Québec–Santé (FRSQ). Mr. Labonté is supported by a CIHR Frederick Banting and Charles Best doctoral fellowship. Dr. Maussion holds fellowships from the FRSQ-INSERM program (Institut National de la Santé et de la Recherche Médicale, France) and from the American Foundation for Suicide Prevention.

From the McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal; the Departments of Psychiatry, Pharmacology and Therapeutics, Human Genetics, and Neurology and Neurosurgery and the McGill Centre for Bioinformatics, McGill University, Montreal; the Singapore Institute for Clinical Sciences, Singapore; and the Molecular Genetics Unit, Institute of Biomedicine of Valencia, Spain.

Address correspondence to Dr. Turecki (gustavo.turecki@mcgill.ca).

Copyright © 2013 by the American Psychiatric Association

Received May 14, 2012; Revised September 24, 2012; Revised November 12, 2012; Accepted November 26, 2012.

Abstract

Objective  Gene expression changes have been reported in the brains of suicide completers. More recently, differences in promoter DNA methylation between suicide completers and comparison subjects in specific genes have been associated with these changes in gene expression patterns, implicating DNA methylation alterations as a plausible component of the pathophysiology of suicide. The authors used a genome-wide approach to investigate the extent of DNA methylation alterations in the brains of suicide completers.

Method  Promoter DNA methylation was profiled using methylated DNA immunoprecipitation (MeDIP) followed by microarray hybridization in hippocampal tissue from 62 men (46 suicide completers and 16 comparison subjects). The correlation between promoter methylation and expression was investigated by comparing the MeDIP data with gene expression profiles generated through mRNA microarray. Methylation differences between groups were validated on neuronal and nonneuronal DNA fractions isolated by fluorescence-assisted cell sorting.

Results  The authors identified 366 promoters that were differentially methylated in suicide completers relative to comparison subjects (273 hypermethylated and 93 hypomethylated). Overall, promoter methylation differences were inversely correlated with gene expression differences. Functional annotation analyses revealed an enrichment of differential methylation in the promoters of genes involved, among other functions, in cognitive processes. Validation was performed on the top genes from this category, and these differences were found to occur mainly in the neuronal cell fraction.

Conclusions  These results suggest broad reprogramming of promoter DNA methylation patterns in the hippocampus of suicide completers. This may help explain gene expression alterations associated with suicide and possibly behavioral changes increasing suicide risk.

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FIGURE 1. Probe Distribution and Relation With Expressiona

a Panel A shows the chromosomal distribution of differentially methylated probes in suicide completers relative to comparison subjects. The upper row shows sites that were hypermethylated relative to comparison subjects, and the lower row hypomethylated. Both hyper- and hypomethylated probes are evenly distributed across the genome. Panel B shows the relationship between gene expression and promoter DNA methylation across the genome. Genes were ordered by level of expression and split into 10 groups, from the lowest 10% to the highest 10%, with each line representing one of these groups (green=low expression; gray=medium expression; red=high expression). Genes with low expression typically have higher promoter methylation levels, whereas genes with high expression typically have lower promoter methylation levels (r=–0.14; p≤4.7×10−247).

FIGURE 2. Heat Map From DAVID Analysis Listing Genes With Differentially Methylated Promoters (rows) and Related Gene Functions (columns)a

a The analysis was conducted using DAVID, version 6.7 (Database for Annotation, Visualization, and Integrated Discovery). In panel A, a green box indicates that the corresponding gene is known to play a role in the corresponding cellular function, and a black box indicates that no such role has been reported. Panel B shows that the total nuclei stained with NeuN generated a bimodal fluorescence intensity distribution. The intensity of fluorescence in the nonneuronal fraction (left blue peak) is less than in the neuronal fraction (right blue peak). The red line represents the intensity of fluorescence generated by the nonspecific fluorophore-conjugated secondary antibody without NeuN antibody.

FIGURE 3. Association of NR2E1 Promoter Methylation Levels With Lower Hippocampal Gene Expression in Suicide Completersa

a Total percent of methylation in NR2E1 promoter in the neuronal cell fraction (panel A; suicide completers, N=35; comparison subjects, N=14) and the nonneuronal cell fraction (panel B; suicide completers, N=46; comparison subjects, N=16). Panel C shows the relative expression of NR2E1 in the hippocampus (suicide completers, N=46; comparison subjects, N=15). In panel D, the graph shows an inverse correlation between NR2E1 mean total % of methylation and NR2E1 relative expression. The graphs in panels E and F show the individual CpG methylation levels in the promoter of NR2E1 in the neuronal and nonneuronal cell fractions, respectively. Values are mean % of methylation, and error bars indicate standard error of the mean. *p<0.05; †p<0.1.

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TABLE 1.List of the Top 25 Differentially Methylated Genes in Suicide Ranked by Corrected p Value
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TABLE 2.Gene Ontology Analysis
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