Genetic variation in DNMT3B and increased global DNA methylation is associated with suicide attempts in psychiatric patients

Abstract

Recently, a significant epigenetic component in the pathology of suicide has been realized. Here we investigate candidate functional SNPs in epigenetic-regulatory genes, DNMT1 and DNMT3B, for association with suicide attempt (SA) among patients with co-existing psychiatric illness. In addition, global DNA methylation levels [5-methyl cytosine (5-mC%)] between SA and psychiatric controls were quantified using the Methylflash Methylated DNA Quantification Kit. DNA was obtained from blood of 79 suicide attempters and 80 non-attempters, assessed for DSM-IV Axis I disorders. Functional SNPs were selected for each gene (DNMT1; n = 7, DNMT3B; n = 10), and genotyped. A SNP (rs2424932) residing in the 3 UTR of the DNMT3B gene was associated with SA compared with a non-attempter control group (P = 0.001; Chi-squared test, Bonferroni adjusted P value = 0.02). Moreover, haplotype analysis identified a DNMT3B haplotype which differed between cases and controls, however this association did not hold after Bonferroni correction (P = 0.01, Bonferroni adjusted P value = 0.56). Global methylation analysis showed that psychiatric patients with a history of SA had significantly higher levels of global DNA methylation compared with controls (P = 0.018, Student's t-test). In conclusion, this is the first report investigating polymorphisms in DNMT genes and global DNA methylation quantification in SA risk. Preliminary findings suggest that allelic variability in DNMT3B may be relevant to the underlying diathesis for suicidal acts and our findings support the hypothesis that aberrant DNA methylation profiles may contribute to the biology of suicidal acts. Thus, analysis of global DNA hypermethylation in blood may represent a biomarker for increased SA risk in psychiatric patients.Keywords: DNA methylation, DNA methyltransferases, epigenetics, polymorphisms, psychiatry, suicide Suicide is a worldwide public health problem and a leading cause of death among young people in developed countries. Every year, almost one million people die from suicide globally with suicide attempts (SAs) up to 20 times more frequent than completed suicide (World Health Organization 2012). The risk for suicidal acts is multi-factorial, and consists of a range of biological, psychiatric, psychosocial, interpersonal and cultural risk factors.In addition to classical genetic abnormalities, an epigenetic component in the pathology of suicide has been realized. Epigenetics can be defined as the mechanisms that initiate and maintain heritable patterns of gene expression without altering the sequence of the genome (Holliday 1987). There are several layers of epigenetic complexity including histone modifications, chromatin remodelling and DNA methylation, the latter being the most thoroughly studied to date (Esteller 2006). DNA methylation refers to the addition of a methyl group to the carbon at position 5 of the cytosine ring, resulting in 5-methylcytosine (5-mC) (Razin & Riggs 1980) and is a key regulatory mechanism of the genome, playing a central role in diverse...

Gene-gene and gene-sex epistatic interactions of <i>DNMT1</i>, <i>DNMT3A</i> and <i>DNMT3B</i> in autoimmune thyroid disease

“…Rs2424932 is present in the 3′-UTR of the DNMT3B gene. In addition, the A/G polymorphism at this locus can create alternative transcription factors binding site (TFBSs), hence it is plausible to suggest that this SNP could potentially alter DNMT3B gene regulation [23]. Rs2424913 is one polymorphism in promoter region of DNMT3B.…”

Impact of DNMT1 and DNMT3a forebrain knockout on depressive- and anxiety like behavior in mice

“…By contrast, using different behavioral and electrophysiological protocols, our laboratory recently reported that forebrain-specific knockout of DNMT3a led to learning and memory deficits and impairments in synaptic plasticity, however DNMT1 KO mice were indistinguishable from control mice (Morris et al , 2014). Recent work in humans and in animal models suggests that aberrant DNA methylation and expression of DNMTs may be causal or contributing factors in a variety of psychiatric disorders including major depressive disorder, anxiety disorders, and schizophrenia (Grayson et al , 2005; Murgatroyd & Spengler, 2012; Chouliaras et al , 2013; Murphy et al , 2013; Hing et al , 2014; Murphy et al , 2015). Indeed, data in humans implicate different DNMT isoforms in the etiology of distinct neuropsychiatric syndromes including suicide (DNMT3b) and schizophrenia (DNMT1) (Grayson et al , 2005; Murphy et al , 2013).…”

“…Recent work in humans and in animal models suggests that aberrant DNA methylation and expression of DNMTs may be causal or contributing factors in a variety of psychiatric disorders including major depressive disorder, anxiety disorders, and schizophrenia (Grayson et al , 2005; Murgatroyd & Spengler, 2012; Chouliaras et al , 2013; Murphy et al , 2013; Hing et al , 2014; Murphy et al , 2015). Indeed, data in humans implicate different DNMT isoforms in the etiology of distinct neuropsychiatric syndromes including suicide (DNMT3b) and schizophrenia (DNMT1) (Grayson et al , 2005; Murphy et al , 2013). Furthermore, a recent study reported that antidepressant medications specifically inhibit the activity of DNMT1 via inhibition of the histone methyltransferase G9a (Zimmermann et al , 2012).…”

Combined effects of DNA methyltransferase 1 and 3A polymorphisms and urinary total arsenic levels on the risk for clear cell renal cell carcinoma

“…Polymorphisms located in introns may affect gene expression by altering mRNA splicing (Moyer et al, 2011), and this could affect cancer susceptibility (Malkinson and You, 1994). A case-control study in a Polish population reported that DNMT1 rs8101626 A N G polymorphism was not associated with ovarian cancer (Mostowska et al, 2013), and Murphy et al did not observe an association between the DNMT1 rs8101626 A N G polymorphism and suicide attempts in psychiatric patients (Murphy et al, 2013). An investigation of the DNMT3A rs34048824 polymorphism found that it did not affect methylation of long interspersed nucleotide elements (LINE-1) in healthy adults in Singapore (Inoue-Choi et al, 2013).…”