Exploratory analysis of genetic variants influencing molecular traits in cerebral cortex of suicide completers

Abstract

Genetic factors have been implicated in suicidal behavior. It has been suggested that one of the roles of genetic factors in suicide could be represented by the effect of genetic variants on gene expression regulation. Alteration in the expression of genes participating in multiple biological systems in the suicidal brain has been demonstrated, so it is imperative to identify genetic variants that could influence gene expression or its regulatory mechanisms. In this study, we integrated DNA methylation, gene expression, and genotype data from the prefrontal cortex of suicides to identify genetic variants that could be factors in the regulation of gene expression, generally called quantitative trait locus (xQTLs). We identify 6,224 methylation quantitative trait loci and 2,239 expression quantitative trait loci (eQTLs) in the prefrontal cortex of suicide completers. The xQTLs identified influence the expression of genes involved in neurodevelopment and cell organization. Two of the eQTLs identified (rs8065311 and rs1019238) were previously associated with cannabis dependence, highlighting a candidate genetic variant for the increased suicide risk in subjects with substance use disorders. Our findings suggest that genetic variants may regulate gene expression in the prefrontal cortex of suicides through the modulation of promoter and enhancer activity, and to a lesser extent, binding transcription factors.

Reduced ribosomal DNA transcription in the prefrontal cortex of suicide victims: consistence of new molecular RT-qPCR findings with previous morphometric data from AgNOR-stained pyramidal neurons

“…The levels of psychotropic drugs were established only in seven suicide victims where medication overdose constituted a cause of death. However, our current study did not aim at analysis of relation between suicide and other mental disorders and our previous studies did not suggest that the decreased rDNA activity in prefrontal pyramidal neurons may be related to the medication used in the last three months of life [13,15].…”

“…deteriorated in the PFC of suicide victims ( [13] and [14], respectively). Disturbed ribosomal function in the PFC in suicide has been highlighted in recent exploratory microarray analysis of genetic variants in suicide completers [15]. As revealed by molecular research, rDNA transcription is attenuated in the hippocampus in cases with a history of child abuse and this effect is related to epigenetic modulations [16], which are also observed in the PFC [17,18].…”

Brain Gene Expression-DNA Methylation Correlation in Suicide Completers: Preliminary Results

“…Brain tissue samples from 21 male suicides and six male non-suicides were analyzed in this study. Male suicide samples have previously been described in Rodríguez-López et al 29 , where the influence of genetic variants in gene expression and methylation profile in suicides was studied. Postmortem brain samples were collected at the Institute of Forensic Sciences in Mexico City, Mexico.…”

Gene Expression Analysis in Postmortem Brains from Individuals Who Died by Suicide: A Systematic Review

“…Molecular markers and processes identified in postmortem designs may reflect a long-standing risk and/or a more proximal precursor of death by suicide [ 5 ]. Specifically, brain tissue has complex patterns of neurochemical and neuroplasticity alterations linked to a variety of psychiatric diseases including suicide [ 6 ]. With regards to completed suicide, several reports have proposed a potential causal impact of a differential gene expression on this complex psychiatric trait [ 7 , 8 ].…”