Sassi, C; (2014) Genetics of Alzheimer's disease: an exploration through exome sequencing. Doctoral thesis , UCL (University College London).

Abstract

Over the past 5 years, whole exome sequencing (WES) ignited a revolution in genomic science, triggering a wave of genetic discoveries that have dramatically improved our understanding of the human genetic landscape. In my research, I have used this innovative approach to explore different facets of the complex genetic architecture of Alzheimer’s disease (AD). First, given the phenotypic overlap between different neurodegenerative dementias such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Alzheimer’s disease, I tested the hypothesis that Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT and PRNP) may influence sporadic Alzheimer’s disease. Second, genome-wide association studies (GWASs) have identified 9 main susceptibility loci for AD (CLU, PICALM, BIN1, EPHA1, ABCA7, MS4A6A, CD33, CR1, CD2AP). Although these have been consistently replicated, the risk variants underlying these GWASs hits still need to be identified, thus I have investigated the whole spectrum of protein-coding variability within these candidate loci. Third, the ‘Amyloid cascade hypothesis’ is the ‘Rosetta stone’ of AD pathology, therefore I have analyzed genes involved in APP-Aß metabolism. Fourth, the discovery of TREM2, the second most significant risk factor for AD. This tremendous finding has been the result of an extensive collaboration and the exome sequencing data that I have generated were the initial foundation of this work. Finally, an increasing body of evidence has shown that causative genes for complex Mendelian syndromes may harbor risk factors for common polygenic diseases. Thus, I have analyzed rare coding variants in Mendelian leukodystrophy genes, as potential susceptibility factors for Alzheimer’s disease. In conclusion, my research emphasizes the pivotal role of rare protein-coding variability in AD genetics. Whole exome sequencing has enabled researchers to explore the human genetic architecture in a comprehensive and unprecedented way, drawing maps of rare coding variability across the human genetic landscape. My doctoral thesis is a reflection of this exciting advancement.

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