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Variants rares et analyse d'exomes : application à la maladie d'Alzheimer du sujet jeune

Abstract : Next-generation sequencing allows studying and analyzing the genetic component part of complexdiseases mediated by rare variants. However, their interpretation represents a major challenge.Indeed, the sequencing of thousands of exomes and genomes revealed the human polymorphismcomplexity and in particular the overrepresentation of rare variants. Despite the development ofsoftwares and variant databases, the prioritization of rare variants remains arduous. My thesis subject was focused on the involvement of rare variants in Alzheimer's disease (AD). From a genetic point of view, AD is caused, in most cases, by a multifactorial determinism, but a minority of cases are autosomal dominant early-onset forms (ADEOAD). The characterization of mutations in the PSEN1, PSEN2 and APP genes as a cause of these Mendelian forms of AD led to the formulationof the amyloid cascade hypothesis, stating that the amyloid-β peptide (Aβ) is triggering the pathophysiological process. In order to detect new genetic risk factors involved in AD, we performed an association study using exome sequencing data from 522 cases with early-onset Alzheimer Disease and 584 controls. The first analyzes focused on single nucleotide variants and short insertions / deletions, and revealed an enrichment in cases of variants that are predicted to be deleterious in the ABCA7 genes. We then then focused on copy number variations (CNVs). The lack of recurrence at the gene-level incited us to work on a gene list. By focusing on the amyloidogenic hypothesis, we built a list of 342 genes involved in the metabolism and toxicity of the Aβ peptide. Thanks to this strategy, we found an enrichment of rare CNVs intersecting this Aβ network in cases.The main result of this CNV study was the identification of a duplication of the 17q21.31 locus in 5patients with a neurodegenerative disease similar to Alzheimer's disease. These patients have aclinical diagnosis of AD, as well as biomarkers and metabolic imaging consistent with an ADneurodegeneration. However, amyloid imaging and neuropathological analysis did not reveal anyamyloid pathology, and were therefore pointing to a pure tauopathy. This CNV study also revealed a partial deletion of the PSEN1 gene, overlapping exons 9 and 10, for which we performed functional studies. We demonstrated that the mutant protein enhanced the production of longer amyloid peptides, the latter being major mediators of Aβ neurotoxicity.
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Kilan Le Guennec. Variants rares et analyse d'exomes : application à la maladie d'Alzheimer du sujet jeune. Psychiatrie et santé mentale. Normandie Université, 2017. Français. ⟨NNT : 2017NORMR148⟩. ⟨tel-01892656⟩

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