- Title
- Utilising high resolution genomics to resolve genetic and epigenetic complexity in schizophrenia
- Creator
- Atkins, Joshua R.
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2019
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Schizophrenia is a common complex neuropsychiatric syndrome with high levels of heritability. Current evidence suggests that the genetic contribution to etiology is comprised from polygenic variation that occur across a broad frequency range including a large proportion of common polymorphisms, down to a small number of those that are extremely rare. A useful tool to capture polygenic burden in complex disorders is Polygenic Risk Scoring (PRS). The utility of this metric has been demonstrated by its ability predictability of case status with respectable accuracy and may even have some clinical utility. While the PRS approach shows promise as a trait biomarker for schizophrenia, it still falls short on sensitivity and specificity measured by receiver operator characteristics. One way to improve the performance is to identify and incorporating more SNPs associated with the disorder through ever large SNP studies, but another alternative would be to include rare variants with known effect size. To explore this further, I investigated the possibility of including schizophrenia associated structural variants into a logistic regression model to see if it could increase case prediction compared to PRS alone. In accordance with expectation, an enhancement in predictive accuracy was observed suggesting that these rare penetrant variants contribute to the risk of the disorder along side the common variant burden. To further investigate the influence of rare variation, whole exome sequencing was carried out for a small subset of the cohort. While this was underpowered to find disease associations, the impact of coding variation was explored more directly by integration with RNA sequencing generated form the same patient derived cells. Interestingly, although loss-of-function variants are rare, they do appear at multiple sites across the genome and impact gene expression. Overall changes in gene expression were observed in the cohort and enriched in a number of pathways including Neutrophil degranulation and Innate Immune System. However, specific cis-acting impact of Copy Number Variants (CNVs) was enriched within the epigenetically imprinted regions at cytoband 15q11.2. Exploratory analysis of the neuroanatomical phenotype of this CNV, gathered through magnetic resonance imaging, was highlighted by decreased thickness in the prefrontal and parietal cortex. Further exploration of LoF variants in a larger proportion of the cohort using whole genome sequencing suggested that those affecting loss-of-function intolerant (pLI) genes (pLI>0.9) are enriched in genes and pathways associated with schizophrenia and neurodevelopmental disorders. These variants, particularly INDELs, were also enriched in a subgroup of cases with severe cognitive symptoms. The observations reported in this thesis supports the hypothesis that schizophrenia is associated with a complex nature of variants from different effect sizes and frequency. Some of these variants are disrupting complex epigenetic regulation and requires further detailed investigations. Thanks to the many advances in technology, today we are starting to understand this complex disorder and offer hope to the patients in need.
- Subject
- neuropsychiatric genomics; genetics; schizophrenia
- Identifier
- http://hdl.handle.net/1959.13/1397812
- Identifier
- uon:34360
- Rights
- Copyright 2019 Joshua R. Atkins
- Language
- eng
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 6 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 354 KB | Adobe Acrobat PDF | View Details Download |