Investigating the genetic factors influencing inflammation, pain and depression in Parkinson’s Disease

Hendry, Hannah 2022. Investigating the genetic factors influencing inflammation, pain and depression in Parkinson’s Disease. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Parkinson’s disease (PD) is a neurodegenerative movement disorder caused by progressive loss of dopaminergic neurons. Beyond motor symptoms, patients experience a host of non-motor symptoms. Two common symptoms are pain and depression, which have been correlated with each other. PD is also characterised by increased activation of the immune system within the periphery and CNS. A genetic risk factor for PD is at the Human Leukocyte Antigen (HLA) locus, a highly polymorphic region encoding proteins that control the adaptive immune response. This project aimed to develop the understanding of genetic factors influencing inflammation, pain, and depression in PD. Firstly, a range of bioinformatics techniques including HLA imputation were applied to a PD dataset to determine the HLA loci most associated with PD risk and protection. This resulted in identification of HLA-B, HLA-C, HLA-DRB1, and HLA-DQA1 as loci to further analyse. The Pacific-Biosciences long-read sequencing method was applied to these loci from PD samples. Results from sequencing data indicated the HLA alleles associated with PD protection (HLA-DRB1*04) and risk (HLA-DQA1*01). These results were compared to HLA imputation in a large case-control dataset, which corroborated the top associated alleles. Secondly, an investigation into the relationship between pain and depression in PD was conducted. Two GWAS of depression in PD were conducted in the UKBB and Proband cohorts, and a GWAS of multisite chronic pain (MCP) in PD was conducted in the UKBB cohort. The results indicated putative genetic associations with these symptoms. Polygenic risk score (PRS) analysis showed no evidence for correlation of genetic influences with MDD, but did for MCP. A Mendelian randomisation analysis was performed, finding no evidence for a causative relationship between these symptoms; this suggests independent causative factors. Overall, novel data to identify potential genetic influences of these PD characteristicswas collected, which can help direct future investigations.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	9 February 2023
Last Modified:	09 Feb 2024 02:30
URI:	https://orca.cardiff.ac.uk/id/eprint/156592

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