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oai:openresearch-repository.anu.edu.au:1885/1068902020-02-05T21:56:29Zcom_1885_9048com_1885_1col_1885_3

Vélez Valbuena, Jorge Iván 2016-07-26T23:47:28Z 2016-07-26T23:47:28Z 2015 b39905275 http://hdl.handle.net/1885/106890 Alzheimer’s disease (AD) is a neurodegenerative disorder that accounts for 60-80% of dementia cases, especially in people over 65 years. More than 36 million people had AD or related dementias in 2010, and more than ~116 million will be diagnosed by 2050. Over the last 30 years, our group has studied the largest multigenerational extended pedigree from the Paisa genetic isolate in which the p.Glu280Ala (E280A) fully penetrant mutation in the Presenilin-1 (PSEN1) gene causes early-onset familial AD (fAD). One of the most intriguing aspects of this pedigree is the broad spectrum of the AD age of onset (ADAOO) that ranges from the earliest 30s to the 80s, and has an average of 48 years. It is hypothesised that genetic variants of major effect (i.e., mutations) modify ADAOO in individuals from this pedigree suffering from early-onset fAD or sporadic AD (sAD). In this thesis, the problem of the ADAOO high variability in this pedigree is tackled by scrutinising functional variants distributed through the whole exomes of individuals with fAD and sAD. Individuals with these forms of AD are descendants from the original founder of the Paisa pedigree and exhibit an extreme phenotype based on the ADAOO for this population. Quality control, filtering, and functional annotation were applied prior to performing association analysis using the multi-locus linear mixed-effects model and collapsing methods to identify common and rare ADAOO modifiers, respectively. Using data mining and predictive modelling tools, a clinical diagnostic tool with potential applications in the clinical setting is developed to predict disease status (early-onset versus late-onset) based on demographic and genetic information. The set of genes harbouring the identified ADAOO modifier variants are involved in physiopathology of AD including neuron apoptosis and apoptotic processes, neurogenesis, dopamine receptor signalling, Wnt protein secretion, the inflammatory processes linked to AD, the negative regulation of glutamergic synaptic transmission, the positive regulation of apoptosis, memory processes, and could be pivotal for prediction, follow-up and eventually as therapeutical targets of AD. en Alzheimer’s disease Age of Onset Extreme Phenotypes PSEN1 E280A mutation Whole-exome Analysis Modifier Genes Alzheimer's disease: Age of Onset Modifier Genes in the World’s Largest Pedigree Thesis (PhD) 6.2.2020 - Made open access after no response to emails re: extending restriction. Arcos-Burgos, Mauricio Department of Genome Sciences, The John Curtin School of Medical Research (JCSMR), The Australian National University submitted by author 27/07/16 Doctor of Philosophy (PhD) 10.25911/5d778ab3cfbe8 mint 2016 open.access