Examining epigenetic variation in the brain in mental illness

Abstract

Mental health represents one of the most significant and increasing burdens to global public health. Depression and schizophrenia, among other mental illnesses, constitute strong risk factors for suicidality which results in over 800,000 deaths every year. The majority of suicides worldwide are indeed related to psychiatric diseases. A growing body of genetic, epigenetic and epidemiological evidence suggests that psychiatric disorders are highly complex phenotypes originating from the multilevel interplay between the strong genetic component and a range of environmental and psychosocial factors. Deeper understanding about the biology of the genome has led to increased interest for the role of non-sequence-based variation in the etiology of neuropsychiatric phenotypes, including suicidality. Epigenetic alterations and gene expression dysregulation have been repetitively reported in post-mortem brain of individuals who died by suicide. To date, however, studies characterizing disease-associated methylomic and transcriptomic variation in the brain have been limited by screening performed in bulk tissue and by the assessment of a single marker at a time. The main aim of this thesis was to investigate DNA methylation and miRNA expression differences in post-mortem brain associated with suicidality and unravel the complexity of epigenetic signals in a heterogeneous tissue like the human brain by developing a method to profile genomic variation at the resolution of individual neural cell types. The results here reported, provide further support for a suicide-specific epigenetic signature, independent from comorbidity with other psychiatric phenotypes, as well as confirming the strong bias perpetrated by bulk tissue studies hence the need to examine genomic variations in purified cell types. In summary, this thesis has identified a) a suicide-specific signal in two different epigenetic markers (DNA methylation and miRNA expression) and b) a protocol to simultaneously profile DNA methylation levels across three purified cell types in the healthy brain highlighting the utility of cell sorting for identifying cell type-driven epigenetic differences associated with etiological variation in complex psychiatric phenotypes.