Alzheimer's disease: Age of Onset Modifier Genes in the World’s Largest Pedigree

dc.contributor.authorVélez Valbuena, Jorge Iván
dc.date.accessioned2016-07-26T23:47:28Z
dc.date.available2016-07-26T23:47:28Z
dc.date.issued2015
dc.description.abstractAlzheimer’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_AU
dc.identifier.otherb39905275
dc.identifier.urihttp://hdl.handle.net/1885/106890
dc.language.isoenen_AU
dc.provenance6.2.2020 - Made open access after no response to emails re: extending restriction.
dc.subjectAlzheimer’s diseaseen_AU
dc.subjectAge of Onseten_AU
dc.subjectExtreme Phenotypesen_AU
dc.subjectPSEN1en_AU
dc.subjectE280A mutationen_AU
dc.subjectWhole-exome Analysisen_AU
dc.subjectModifier Genesen_AU
dc.titleAlzheimer's disease: Age of Onset Modifier Genes in the World’s Largest Pedigreeen_AU
dc.typeThesis (PhD)en_AU
dcterms.valid2016en_AU
local.contributor.affiliationDepartment of Genome Sciences, The John Curtin School of Medical Research (JCSMR), The Australian National Universityen_AU
local.contributor.authoremailjorgeivanvelez@gmail.comen_AU
local.contributor.supervisorArcos-Burgos, Mauricio
local.contributor.supervisorcontactMauricio.Arcos-Burgos@anu.edu.auen_AU
local.description.notessubmitted by author 27/07/16
local.identifier.doi10.25911/5d778ab3cfbe8
local.mintdoimint
local.type.degreeDoctor of Philosophy (PhD)en_AU

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