Federoff, MC; (2017) An investigation into the genetic architecture of multiple system atrophy and familial Parkinson's disease. Doctoral thesis , UCL (University College London).

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Abstract

Within the past decade, significant genetic underpinnings of devastating neurological disorders including Parkinson’s disease (PD), Alzheimer’s disease (AD) and Amyotrophic Lateral Sclerosis (ALS) have all been illuminated through advanced genomic technologies. Such discoveries have been facilitated by genome wide association (GWA) studies and next generation sequencing (NGS) investigations in order to identify common variants and rare variants, respectively, which contribute to disease risk. This thesis aims to extend these analyses to an understudied disease, multiple system atrophy (MSA), and to investigate the genetic basis of an apparent cluster of PD cases in Greece. Thus, I plan to accomplish three main goals in my thesis: First, I would like to determine if common variants are associated with MSA risk through heritability analysis and if so, can these be identified through imputation of GWA study data using greater than 900 sporadic MSA cases. While common variants harboring an association with MSA may be either protective or deleterious, any significant findings will yield insight into the pathogenesis of disease. Secondly, I would to identify candidate variants and gene-based variability that are associated with MSA using next generation sequencing in approximately 415 samples, about half of which are pathologically confirmed. Ideally, these will be putative causal variants that will shed light on the molecular mechanisms of disease and potential for therapeutic design in the future. However, it is feasible that such rare variants may modulate risk for MSA development. Because MSA is a rare disease systematic investigation of the genetic basis of this disease has been challenging; the cohorts studied are small and thus lack power. Hence, the goal of this work is to produce rational evidence based candidate genes and variants for validation and replication by the MSA research community. This will be a cardinal step towards our understanding of the genetic basis of this severely debilitating and fatal neurodegenerative disorder. Thirdly, I would like to further explore the genetic architecture of Parkinson’s disease among a large Greek kindred that we believe has maintained a high degree of genetic isolation for the last several centuries. While we have identified several risk factors and causal variants associated with Parkinson’s disease, heritability estimates suggest that other genetic variants remain to be found. By utilizing some of the most advanced technological approaches in genetics, I hope to elucidate a missing piece of the puzzle in the etiology and molecular underpinnings of this devastating disease.

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