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Using whole exome sequencing data to elucidate the role of structural variation in schizophrenia

Bakewell, Jack 2023. Using whole exome sequencing data to elucidate the role of structural variation in schizophrenia. PhD Thesis, Cardiff University.
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Large, rare structural variants (SVs) have consistently been shown to confer liability for schizophrenia. However, almost all previous studies have been based on data derived from genotyping microarrays, which can only be used to detect a small number of SV types and have limited utility for identifying variants at the smaller end of the size spectrum (<100kb). Therefore, I assessed whether data derived from whole exome sequencing (WES) can be used to identify SVs in schizophrenia that have hitherto gone undetected. To do this, I applied two structural variant callers, CLAMMS and InDelible, to the WES data of two in-house samples for which SVs had previously been called using array data. As each caller mines a different aspect of WES data, they are sensitive to different types and sizes of SVs. The first WES dataset I applied these methods to is derived from a trios sample consisting of 616 schizophrenia probands and their parents. Both callers identified de novo SVs that were not detected in the array data, some of which overlapped genes that have been implicated in previous studies of schizophrenia or are plausible candidate risk genes. The second dataset was generated from 927 schizophrenia cases who have been extensively tested for cognitive ability. Subsets of small (<100kb), rare SVs generated by both callers were found to be associated with cognitive deficits, indicating that SVs previously undetected in the array data are implicated in schizophrenia symptomology. My thesis therefore provides evidence that WES data can be used to detect SVs under-reported in the literature that may have a role in schizophrenia.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Funders: MRC
Date of First Compliant Deposit: 4 October 2023
Last Modified: 04 Oct 2023 11:53

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