Abstract5Thisthesisaimedto uncover some of themore precise mechanisms by which genetic loci may influenceneuropsychiatric susceptibility. Iaim to identify genetic susceptibility for neuropsychiatric disorders using quantitativetraits such as behaviourand neuroimaging parameters, which may help toindex subclinical componentspresent across severalneuropsychiatric classifications. Iprobespecific neural networks/parameters of neurocognition; hypothesisingto witness larger and more specific effects than assaying global parameterssuch as IQandbrain volume.I aim to uncover novel mechanisms by which some of the most intriguing genetic polymorphisms identified from recent genetic discoveries may modulate susceptibility.
The first studyprovides evidence suggesting that a common genetic variant hypothesized to modulate dopamine levels (COMT),may account for individual differences in the brain’s global valuation system, which may then mediate susceptibility to a host of neuropsychiatric illness characterised by deficits in reward processing. Thesecond study providesevidence that genes identified by agnostic approaches (genome-wide association studies) may have a role in neurobiological pathways mechanistically linked to disorders such as schizophrenia/psychosis. I showa component of the working memory network for emotional faces is modulated by a variant on the ZNF804Agenein a manner that mirrors the disruptions seen in patients with schizophrenia.
The third study demonstrates that a variant on the CLUgene may modulate susceptibility to Alzheimer’s disease in a similar functional manner towell-established genetic variants such as APOE.The study contributes to a body of knowledge suggesting that using neuroimaging, it is possible to Abstract6witness theassociation between genetic susceptibility to Alzheimer’s disease and compensatoryneurobiological changes, decades before the manifestation of clinical symptoms. Based on the progression in the field of behavioural/imaging genetics and the discoveries within this thesis, I concludeby discussingthe efficacy of tools such as behaviour/neuroimaging measures in the processes of linkinggenetic variance to neurobiological pathways to behaviour. I also show how the experimental studies in this thesis embed in present literature and replicate/converge withindependent data. We must identify appropriate techniques to understand the nature of genetic susceptibilityand classifyspecific neurobiological specific domains of heritable neurocognition. Once we can reliably link gene variants to specific domains ofneurocognition,we can identify mechanistic links between genetic suspect abilityand symptomology. These developments will help us consider therapeutic interventions for neuropsychiatricsymptoms/states and develop risk prediction/reductionstrategies.