Martinez-Carrasco, Alejandro; (2024) Multi-omics and clinical study of Parkinson's disease and progression. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Parkinson’s disease (PD) is a progressive neurological condition that can be measured using clinical scales. Features of PD progression include motor and cognitive decline, as well as the emergence of motor fluctuations such as levodopa-induced dyskinesias. Although some patients follow a common progression trend, there is significant heterogeneity, with some patients progressing more quickly and exhibiting distinct clinical features. This heterogeneity is also notable at disease onset. I hypothesised that PD progression might be explained by common genetic variability. During my PhD, I performed longitudinal genome-wide association studies (GWAS) to understand the genetic basis of motor progression and the time to develop dyskinesias, a motor fluctuation influenced by PD onset and chronic levodopa treatment. Additionally, I conducted a large-scale disease severity analysis using 10 different clinical instruments. For this large-scale analysis I used long-gwas, an end-to-end Nextflow pipeline to conduct cross-sectional and longitudinal GWAS. Based on these GWAS approaches, I identified several loci significantly associated with prognosis, severity and survival. Applying functional annotation analyses to decode GWAS, I successfully nominated genes to be associated with the outcomes at most GWAS significant loci. I nominated the ACP6 gene to be associated with the progression of axial PD motor features, and MAD1L1 and SOX9 genes to be associated with the severity of axial PD motor features. In addition, I nominated the LRP8, XYLT1, and DNAJB4 genes as associated with the time to develop dyskinesias in PD. Notably, I validated three novel loci (SERGEF, OTUD7A, SCN1A) associated with the severity of hyposmia, alongside previously reported LRRK2 and GBA1 genes, involved in the autophagy-lysosomal pathway which may serve as surrogates for α-synuclein pathology. Finally, I conducted a cell-type enrichment analysis of PD progression and susceptibility using publicly available longitudinal GWAS cell type expression data. We found a significant association between genes implicated in PD motor progression and microglia. Furthermore, we proposed a new framework for cell type enrichment that efficiently incorporates information about cis-regulation of gene expression.

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