Neurocognitive effects of risk variants for psychosis: neuropsychological and neuroimaging studies of variants and pathways
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Schizophrenia is a complex, highly polygenic brain disorder. Cognitive deficits in schizophrenia are among the most disabling symptoms, and as of yet, have no effective treatment. Investigating the effect of genetic variants on cognitive performance may point towards biological mechanisms behind this deficit, potentially leading to a better understanding and treatment of the disorder. Genome-wide association studies (GWAS) have provided extensive data showing associations between over 100 genetic loci and schizophrenia, however, these genetic studies cannot establish the biological significance of these associations. To build on these findings, the functional consequences through which these variants increase this liability need to be established. This thesis explores the functional consequences of carrying certain genetic variants on cognitive performance in patients and healthy participants, extending beyond GWAS findings. The first study was performed to investigate the association between 11 common genetic variants associated with synaptic transmission genes and the cognitive deficits commonly seen in schizophrenia patients. The schizophrenia-associated G allele of rs2007044 (a SNP within the gene for the calcium channel subunit 1αc, CACNA1C) was associated with poorer memory performance in our sample and two additional replication samples. During a fMRI spatial working memory task, the same risk allele was associated with decreased functional connectivity between the right dorsolateral prefrontal cortex and three other regions. Two other SNPs (rs7893279 located within the gene for calcium channel subunit B2, CACNB2, and rs1339227, linked to the gene RIMS1 involved in synaptic vesicular exocytosis) were associated measures of social cognitive ability. The second study was based on a polygenic risk score (PRS), constructed from a list of identified SZ-risk genes empirically regulated by the schizophrenia-risk gene MIR137. Increased polygenic risk was associated with significantly lower performance on IQ, working memory, xi and episodic memory. Increasing PRS was also associated with increased neural activation during a fMRI spatial working memory task. Based on the strong association between this PRS and cognitive performance observed in the second study, particularly in memory domains, the effect of the MIR137 PRS on structural correlates of memory was investigated in the final study. No association between MIR137 PRS and measures of cortical thickness, surface area, or hippocampal volume was observed. There was a marginally significant association between PRS and total brain volume. Findings indicate an involvement of genes related to the overall synaptic transmission process and regulation of synaptic properties in cognitive function, rather than any specific neurotransmitter. These findings make a significant contribution to the area of psychiatric genetics by reporting the first endophenotypic characterisation of these 11 SNPs, and the broader downstream effects of MIR137, on neuropsychological and neuroimaging measures.
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