Genetic Contribution to Heterogeneity in Brain Morphology with Applications to Schizophrenia
Year: 2014
Type: dissertation
Study design: Observational Study
Abstract: Schizophrenia is a highly heterogeneous disorder. Differences among patients with schizophrenia have been reported in clinical features, cognitive functioning, and brain structure. This thesis investigates the impact of the well supported genetic risk variants on brain structure and also considers the role of imaging-genetic changes on heterogeneous phenotypes relevant to schizophrenia. In the first study, the genome-wide supported NRXN1 gene, associated with schizophrenia and autism spectrum disorders, was examined with magnetic resonance imaging (MRI) volumetric measures and measures of sensorimotor function. Study two investigated the effect of the genome-wide identified schizophrenia risk variant in the MIR137 gene for association with age-at-onset and brain structures implicated in disease severity, as well as white matter fractional anisotropy (FA) and cortical thickness. Risk allele carriers had earlier age-at-onset and aberrant brain structure suggesting that MIR137 may predict a more severe schizophrenia subphenotype. Study three examined the role of the GAD1 gene on brain structure and executive function. Among patients and controls the GAD1 variant predicted changes in white matter FA and multiple working memory tasks. Using voxel-wise mediation analysis, we were able to infer the functional relevance of GAD1 on structural connectivity by showing these FA changes statistically cause impaired working memory performance. In the final study, we investigated relationships among polygenic additive risk, brain-wide measures, and cognition in schizophrenia patients and healthy controls. Schizophrenia patients with low polygenic risk were similar in brain structure and cognitive performance to healthy controls. In contrast, high polygenic risk in patients led to large reductions in cortical thickness and white matter skeleton FA, in addition to impaired semantic memory and motor functioning. Taken together, these studies suggest that neuroimaging and genetics can be used to meaningful disentangle heterogeneity of schizophrenia phenotypes, and may move towards neurobiological based treatment options.
Source: TSpace (University of Toronto)
Author: Tristram A. Lett
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2583455674