Advances in single nucleotide polymorphism (SNP) genotyping technologies have
revolutionised our ability to scrutinise the human genome. My PhD research focuses on
using these new technologies to catalogue genetic variability in a collection of diverse
populations from around the globe, and to determine the role of genetic variants in
neurological diseases. First, I present and discuss the analysis of genome‐wide SNP data
in individuals from ethnically and geographically diverse human populations uncovering
the diversity of genotype, haplotype and copy number variation in these populations.
Second, I will describe an autozygosity mapping approach in three Brazilian dystoniaparkinsonism
families which lead to the identification of a novel disease‐segregating
mutation in the gene PRKRA. Third, I will report on a large genome‐wide association
study in Parkinson’s disease, uncovering genetic variability at the SNCA and MAPT loci
that are strongly associated with risk for developing disease. Forth, I provide compelling
evidence that genetic variants at the SNCA locus are also significantly associated with
risk for developing multiple system atrophy. This finding represents the first
reproducible risk gene for this devastating disorder, and causally links this condition to
the more common neurodegenerative disorder Parkinson’s disease. Finally, I present
the results of a comprehensive mutational screening study investigating the frequency
and spectrum of sequence and copy number mutations in the parkinsonism genes
PRKN and PINK in individuals with early-onset Parkinson’s disease, in multiple system
atrophy patients and in normal controls. In summary, the data presented in this thesis
emphasise the critical role that genetic variability plays in the pathogenesis of
neurological disorders
