Integrative DNA Methylation and Gene Expression Analysis in the Prefrontal Cortex of Mexicans who died by Suicide.

Background Suicide represents a major health concern, especially in developing countries. While many demographic risk factors have been proposed, the underlying molecular pathology of suicide remains poorly understood. A body of evidence suggests that aberrant DNA methylation and expression is involved. In this study, we examined DNA methylation profiles and concordant gene expression changes in the prefrontal cortex of Mexicans who died by suicide. Methods In collaboration with the Coroner's office in Mexico City, brain samples of males who died by suicide (n=35) and age-matched sudden death controls (n=13) were collected. DNA and RNA were extracted from prefrontal cortex tissue and analyzed with the Infinium Methylation480k and the HumanHT-12 v4 Expression Beadchips, respectively. Results We report evidence of altered DNA methylation profiles at 4,430 genomic regions together with 622 genes characterized by differential expression in cases versus controls. Seventy genes were found to have concordant methylation and expression changes. Metacore enriched analysis identified ten genes with biological relevance to psychiatric phenotypes and suicide (ADCY9, CRH, NFATC4, ABCC8, HMGA1, KAT2A, EPHA2, TRRAP, CD22, CBLN1) and highlighted the association that ADCY9 has with various pathways, including, signal transduction regulated by the cAMP-responsive element modulator, neurophysiological process regulated by the corticotrophin-releasing hormone and synaptic plasticity. We, therefore, went on to validate the observed hypomethylation of ADCY9 in cases versus control, through targeted bisulfite sequencing. Conclusion Our study represents the first analysis of DNA methylation and gene expression associated with suicide in a Mexican population using postmortem brain, providing novel insights for convergent molecular alterations associated with suicide.