Investigating functional and genetic interactions underlying schizophrenia risk in 22q11.2 Deletion Syndrome

Moylett, Aine 2020. Investigating functional and genetic interactions underlying schizophrenia risk in 22q11.2 Deletion Syndrome. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

22q11.2 Deletion Syndrome (22q11.2DS) is a genetic disorder caused by a hemizygous deletion at chromosome 22q11.2. It is the most common chromosomal microdeletion and the strongest known molecular genetic risk factor associated with schizophrenia. However, the underlying mechanisms that lead to this neuropsychiatric risk remain largely unknown. The work in this thesis sought to investigate possible genetic and functional mechanisms that contribute to schizophrenia risk in 22q.11.2DS. Potential schizophrenia candidate and disease modifier genes from within and outside of the 22q11.2 deletion region were explored. From within the deletion, DGCR8 was initially selected as a gene of interest due to its key role in the microRNA biogenesis pathway and therefore gene expression regulation. Additional candidate genes were identified by assessing gene co-expression during fetal development in relation to DGCR8 and predicated of loss of function and happloinsuffiency intolerance, leading to the selection of HIRA and ZDHHC8. Transcriptome wide association studies were performed in disease relevant tissues to identify schizophrenia modifier genes outside of the deletion by comparing 22q11.2DS patients with and without schizophrenia. However, this analysis identified no significant differences in gene expression. CRISPR/Cas9 genome editing technology was utilised to knockout DGCR8 in human embryonic stem cells. Mutant lines were generated and differentiated into cortical neuroprogenitor cells to investigate the role of DGCR8 in neurodevelopment. This work provided further evidence that DGCR8 knockout lines derived from human embryonic stem cells may not be a viable method of modelling due to genomic instability, lack of protein reduction and so insufficient disease recapitulation. Finally, a lentiviral based CRISPR/Cas9 system in human neuroprogenitor cells (hNPCs) was established. Genetic manipulation of DGCR8 in hNPCs further indicated a relationship between DGCR8 and TBR1 in cortical development. This thesis combines bioinformatic and cellular approaches to provide a basis for investigation of mechanisms underlying schizophrenia risk in 22q11.2DS.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	2 March 2021
Last Modified:	19 Apr 2023 08:28
URI:	https://orca.cardiff.ac.uk/id/eprint/139095

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