Mok, KYB; (2013) Genetics of Neurodegenerative Disease -- A Genome-Wide Approach. Doctoral thesis , UCL (University College London).

Abstract

Neuro-degenerative diseases present an increasingly heavy burden in our ageing population. Genetic factors play an important role in the aetiology of the neuro-degenerative diseases. Dissecting the underlying genetic mechanism gives us vital clues to the pathophysiology, and ultimately helps us develop novel therapeutic interventions. Recent technological advances in genotyping genetic variants and bioinformatics have revolutionized the approach to the study of genetic diseases. The initial major advance was the accurate genotyping and data processing for hundreds of thousands single nucleotide polymorphisms simultaneously. Studies on the association between these polymorphisms, mostly common variants, and complex diseases became feasible. The association can shed light to the pathophysiology. My thesis rides on these developments, applying them to the study of genetics in neurodegenerative diseases. The first part of the thesis is a pilot study on genetics of cervical dystonia, using a genome-wide association approach. Given the small sample size, no statistically significant results were identified. A few potential loci were suggested after imputation. The second part is a study on amyotrophic lateral sclerosis. Meta-analysis was performed on five recently published genome-wide association studies. A follow-up haplotype analysis was carried out on these cohorts, comparing this with data available from familial studies. A single founding haplotype leading to amyotrophic lateral sclerosis was proposed. Subsequent identification of the causal gene, C9orf72, within the haplotype region by our collaborators led to further phenotyping studies. The third part describes a copy number variant analysis of idiopathic Parkinson’s disease. The study was based on the genome-wide association data in the UK cohort in comparison to other cohorts. Chromosome 22q11.2 heterozygous deletion was found to play an important role in the aetiology of Parkinson’s disease. This thesis demonstrates that utilization of emerging genetic technology has advanced our understanding of some of the genetic factors predisposing to these neurodegenerative diseases.

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