Perturbed molecular pathways in Parkinson's disease

Thesis

Parkinson's Disease (PD) is the most common movement disorder and second most common neurodegenerative disorder, affecting 1 in every 100 people over the age of 60. It is a heterogeneous disorder whose pathology and causes remain incompletely understood. Identification of genetic risk factors can provide valuable understanding of the disease process and pave the way for the development of novel treatment.

Firstly, eQTLs were identified that affected the expression of functionally related PD-linked gene pairs and were within PD associated genomic regions. This was achieved by integrating multiple data sources into a network tailored to PD, then interrogating this in tandem with genome-wide association study and eQTL data. Four eQTLs were identified, two affecting LRRK2. The genotype conferring greatest additive increase in LRRK2 expression was significantly over-represented among two independent case populations but not among controls.

Secondly, Copy Number Variants were classified by their functional annotations to identify common molecular pathways on which PD-linked variation converged. Seven pathways were enriched among PD patients, two of which remained so after independently significant variation within PARK2 was removed. However this was not replicated in an independent cohort.

Thirdly genome-wide association studies were carried out first comparing PD case and control and second comparing phenotypic subtypes among PD cases. Enrichment analysis identified two pathways significantly associated with disease onset and implicated a subset of one with a specific phenotypic subgroup.

Finally, continuous phenotypic variation was analysed. Phenotypic axes were identified each representing multiple co-varying phenotypes. Genome-wide genetic analyses of these identified 10 genomic regions significantly affecting the severity of specific measured phenotypes.

This work implicates genetic variation in mediating both PD onset and phenotypic progression and yields insight into the common molecular pathways that may be involved. A novel method of quantifying patient phenotype was also developed that should facilitate future analysis.

Authors: Millin, S

• DOI: 10.5287/ora-r5z0dqxnm
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English