Rare variants in nucleotide methylation genes and neurodevelopmental disorders

Parke, Adam (2019) Rare variants in nucleotide methylation genes and neurodevelopmental disorders. MRes thesis, University of Nottingham.

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Nucleotide methylation has a function in genomic repair, and in the regulation of transcription and translation. DNA methylation processes have been previously associated with developmental delay, dementia and neuronal death phenotypes. RNA methylation, a field in its infancy, has been associated with cancer and neurological disorders. However, much of this research is still in its early stages. Using next-generation sequencing data to screen DNA and RNA methylation genes, this thesis aims to investigate nucleotide methylation and genetic risk for neurological and neuropsychiatric diseases.

Using UK10K project for multiple intellectual disability and autism spectrum disorder disease datasets, a candidate gene set of 30 DNA and RNA methylation genes was interrogated for Loss of Function (LoF) variants. I identified 8 loss of function variants in individuals with intellectual disability and autism spectrum disorder. These loss of function variants were found in genes which remove or modify methyl modifications on DNA or RNA. In a second part of this thesis, a candidate gene set of 37 DNA and RNA methylation control genes was screened for missense as well as LoF variants in multiple UK10K schizophrenia cohorts. I found 15 loss of function variants in individuals with schizophrenia and identified 8 missense variants that were found to show significant differences in allele frequencies in the case-control analysis. Assessing load burden analysis, the gene TDG, which contained a significant missense variant (V367M), was also found to be significantly enriched (p = 2.85 x 10-33).

These results suggest an association between coding variants in DNA and RNA methylation genes with risk for neurodevelopmental disorders such as autism spectrum disorder, intellectual disability and schizophrenia. These findings also clearly indicate a need for future research which examines the full spectrum of DNA and RNA modification methylomes in individuals with neurological and neuropsychiatric disorders.

Item Type: Thesis (University of Nottingham only) (MRes)
Supervisors: Knight, Helen
Armour, John
Keywords: Nucleotide methylation; Methylation genes; Genetic risk; Modification methylomes
Subjects: Q Science > QP Physiology
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID: 56385
Depositing User: Parke, Adam
Date Deposited: 08 Aug 2019 10:07
Last Modified: 19 Apr 2021 13:19
URI: https://eprints.nottingham.ac.uk/id/eprint/56385

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