Epigenetic dysregulation in relation to psychiatric traits in adolescence and adulthood

Abstract: Epigenetics has evolved into a key research focus in the field of psychiatry. DNA methylation is the most researched epigenetic mechanism. In paper I-III, 130 and 93 adolescents were randomly recruited at two separate intervals. Subjects were evaluated by web-based diagnostic interviews using the Development and Well-Being Assessment (DAWBA), providing computer generated diagnostic predictions of probability of diagnosis, covering several psychiatric disorders. For Paper I-II, the genome-wide DNA methylation pattern was measured from whole blood using the Illumina 450K array, and for paper IV by the Illumina EPIC BeadChip. In paper I, a methylome-wide association study (MWAS) was conducted (n=93) followed by a validation analysis (n=78), contrasting methylation levels in groups stratified by DAWBA depression risk scores. A microRNA4646 (MIR4646) associated methylation locus was differentially methylated in the MWAS (pbonf<0.05) and results were replicated in the validation cohort (p<0.05). Methylation levels at the identified locus correlated inversely with gene expression levels of MIR4456 (p<0.05). In silico analysis suggests MIR4646 may influence synthesis of omega-3 fatty acids, previously implicated in major depressive disorder. In paper II, 37 single nucleotide polymorphisms (SNP:s) previously associated with psychiatric disease were evaluated in relation to genome-wide DNA methylation levels in 130 adolescents in a methylome-wide (mQTL) analysis. Five SNP-CpG pairs were identified (pbonf<0.05) and replicated (p<0.05). Methylation of three of these were shown to be significantly correlated with gene expression levels of the associated genes (p<0.05). One identified GAD1-coupled methylation site was differentially methylated to a general psychiatric risk score in adolescents (p<0.05). In Paper III, hypothalamic-pituitary-adrenal (HPA)-axis coupled DNA methylation loci were investigated in 88 suicide attempters to identify associations to severity of suicide attempt. One corticotropin releasing hormone (CRH)-associated CpG-site was significantly hypomethylated in the high-risk group of suicide-attempters (n=31)(cg19035496, p<0.001) and exhibited hypermethylation in an external study group of adolescents in dependency of a general psychiatric risk score (p<0.05). In paper IV, 8,852 microRNA (miRNA) associated CpG-sites were investigated for an association with hypersexual disorder (HD). A microRNA-4456 (MIR4456) associated CpG-site (cg01299774) was borderline significant in HD (pFDR=5.81E-02) and differentially methylated in alcohol dependence (p<0.05) in an independent study group. Methylation levels at cg01299774 correlated inversely with expression levels of MIR4456 (p<0.01) and MIR4456 was lower expressed in HD (p<0.05). In-silico analyses suggests MIR4456 putatively targets genes preferentially expressed in brain and that are involved in major neuronal molecular mechanisms thought to be relevant for HD, e.g., the oxytocin signaling pathway.