Association of the SAT1 in/del polymorphism with suicide completion

Abstract

Several studies have observed decreased expression of spermidine/spermine N1-acetyltransferase (SAT1) in the brains of suicide completers, and we previously identified a single-nucleotide polymorphism in the promoter region of SAT1 which was associated with suicide completion and SAT1 expression in the brain. We recently characterized the haplotype structure of the SAT1 promoter region and identified an insertion/deletion (in/del) of 15 adenine residues. This variant appears to be a predictor of SAT1 expression, and we were thus interested in determining if the lower expressing deletion allele was found more frequently among suicide completers. To this end, we genotyped the in/del in a sample of 771 French-Canadian males, comprising 326 suicide completers and 445 non-suicide controls. We found no significant difference in the frequencies of the two alleles between suicide completers and controls in the entire sample. However, we observed a significantly higher frequency of the deletion in the depressed suicide completers compared to the depressed non-suicides. These results add support for a role of SAT1 in conferring a risk for suicide completion, in particular in the context of depressive disorders.

Isoform-level brain expression profiling of the spermidine/spermine N1-Acetyltransferase1 ( SAT1 ) gene in major depression and suicide

“…Despite accumulating evidence implicating SAT1 in depression and/or suicide (Sequeira et al, 2006; Fiori et al, 2009, 2010; Guipponi et al, 2009; Klempan et al, 2009b; Fiori and Turecki, 2010a,b, 2011; Le-Niculescu et al, 2013; Lopez et al, 2014) including the current report, the mechanistic relationship between SAT1 expression, polyamine contents with depression and suicide remains unclear. Constitutively lower brain SAT1 expression in MDD could either be a result of, or directly contribute to, maladaptive polyamine stress response (PSR) during chronic stress (Gilad and Gilad, 2003).…”

“…SAT1 is arguably one of the most consistently implicated genes in depressed suicides based on cDNA microarrays (Sequeira et al, 2006; Fiori et al, 2009, 2010; Guipponi et al, 2009; Klempan et al, 2009b; Fiori and Turecki, 2010a,b, 2011; Le-Niculescu et al, 2013; Lopez et al, 2014), but it is unknown whether this gene is involved in MDD independently of suicide, which isoforms in particular are dysregulated, and whether the gene undergoes differential splicing in suicide and depression. In the current study, we applied NGS whole-transcriptome profiling (RNA-Seq) and examined SAT1 gene-level, isoform-level and exon-level expression in major depressive disorder (MDD) with and without suicide.…”

Understanding epigenetic architecture of suicide neurobiology: A critical perspective

“…However, a significant relationship was observed between SMOX expression and a specific site based hypermethylation on its promoter. The outcome of this study appeared to be rather surprising from DNA methylation standpoint, but it could possibly be explained considering the very small population size which might have less ability to resolve the distinctive effect of methylation alteration (Fiori and Turecki, 2010). …”

“…Over the last few decades, extensive studies to elucidate the intricacies of dysregulated neurotransmission in psychiatric illnesses, potentially leading to suicidal behavior, have shifted the focus from monoaminergic hypothesis to other molecular pathways including noradrenergic, glutamatergic and γ-aminobutyric acid (GABA) neurotransmission, as well as the polyamine system in post-mortem brains (Fiori and Turecki, 2010). …”

“…Careful observations unveiled few more genes namely SMS, SMOX and AMD1 as differentially expressed candidates in suicide completers (Guipponi et al, 2009; Sequeira et al, 2006; Sequeira et al, 2007). With a growing need to underpin the functional relationship, Fiori and group (2010) hypothesized the possible subduing impact of promoter DNA methylation as a causal factor on observed attenuated expression of two of the previously mentioned polyaminergic genes, SMS and SMOX in prefrontal cortex of suicide completers (Fiori and Turecki, 2010). Brodmann area 8/9 based analysis of SMS and SMOX genes within 1kb upstream of their promoter region revealed either low level of methylation or complete unmethylated state in 10 cases of suicide completers.…”