Main Research Objectives

The overarching goal of the work contained in this thesis was to expand our knowledge of the genetic architecture underlying mental health symptoms and the brain functional connectome, with a particular focus on understanding the interplay within and between these. We aimed to achieve this goal by addressing each of the following research challenges:

• Previous studies indicate that psychiatric disorders are phenotpyically and genetically correlated. Yet it remains unclear if this is largely due to the overlap of symptoms between disorders or some shared underlying mechanism. Using a large public repository, we used a statistical framework to derive symptom profiles that are phenotypically independent, and studied their genetic associations through the GWAS approach, as well as the associations with psychiatric disorders. This allowed us to assess the genetic correlation between psychiatric symptoms in the absence of phenotypic correlation.
• A variety of imaging modalities, among which functional connectivity, have been linked to both genetics and psychiatric disorders, but the nature of these relations remains elusive. In this study we create a genetic map of the brain functional connectome and the overlapping genetics with psychiatric disorders that allows us to leverage the known associations to disentangle these associations. Again, using a large public repository that contains both imaging and genetic data, we construct a multivariate measure of brain functional connectivity in a population sample. We then compare the genetic profile from the brain functional connectivity with publicly available summary statistics from a number of psychiatric disorders to highlight shared genetic determinants. Functional mapping of these shared genetic loci will provide us with better insights into the biological processes involved in both the brain functional connectome and psychiatric disorders and show that the associations are not simply an artifact of statistics.
• Given the genetic associations with symptoms relevant for mental health and functional connectivtiy, the question remains whether the associations shown before hold outside the current diagnostic categories. To uncover to what degree the established associations can be linked to shared symptoms, we investigate the overlapping genetics between the brain functional connectome and the aforementioned symptom profiles. This will provide insight into the shared genetics between the brain functional connectome and symptoms in a population sample. This knowledge can extent to help increase understanding of psychiatric condititions.