Functional epigenetic analyses in the context of psychiatric health in adolescence

Sammanfattning: Adolescence is a unique and formative period for learning and developing skills and abilities for adulthood. The prevalence of mental health problems in adolescents is estimated to 10-20%, being a major risk for suicide, social and academic impairments. Suicide is the third leading cause of death in older adolescents (15-19 years). Genetic studies suggest that gene-environment interaction contributes to molecular mechanisms of the differential risks for psychiatric disorders and epigenetic marks such as DNA methylation (DNAm) and non-coding RNA (ncRNA) are likely involved. In this doctoral thesis, we investigated how the environmentally modifiable factors are associated with genetic variation, anxiety disorders, depression and suicidal behavior. Using well described bioinformatic and statistical methods, e.g. DNAm preprocessing techniques, gene ontology enrichment, chromatin state inference, correlation of DNAm in blood and brain tissues and eQTL effect, we uncovered functional differential DNAm, meQTL and eQTL associations in the context of depression, generalized anxiety and suicidal thoughts in multiple datasets. First, in an epigenome-wide study, we identified associations between psychiatric-related SNPs and DNAm at CpG sites located within enhancer regions in hippocampus. Then, using a targeted approach by including CpG sites with cross tissue relevance, we found and replicated an association between differentially DNAm at one genomic locus and risk for generalized anxiety disorder. The functional role of the CpG site was supported by the observed association between DNAm shifts and mRNA expression in blood, together with its location within regulatory chromatin state in brain. In a longitudinal epigenome-wide study, we identified changes in DNAm levels at the gene promoter for risk for depression. Moreover, in blood, DNAm at one CpG site was associated with suicidal behavior and mRNA expression, which may be genetically controlled. These findings could be translated in the brain as differentially DNAm and mRNA expression levels at the same locus were observed for major depression in post-mortem tissue brain. Lastly, we identified meQTL and micro-RNA (miRNA) eQTL involved in depression in whole blood and brain. Gene ontology terms of the predicted target genes for one miRNA involved behavioral fear and defense response, presynaptic signal transductions, and presynaptic active zone organization. Overall, this thesis investigated and demonstrated a complementary influence of genetic and epigenetic factors underlying pathogenesis of psychiatric disorders.