Populatie-gebaseerde nieuwe generatie sequentiebepaling in de ontrafeling van de complexe genetica van Alzheimer dementie
6 oktober 2017
UAntwerpen, Campus Drie Eiken, Gebouw Q, Promotiezaal - Universiteitsplein 1 - 2610 Wilrijk (Antwerpen) (route: UAntwerpen, Campus Drie Eiken
16 - 18 uur
Doctoraatsverdediging Johannes Verheijen - Departement Biomedische Wetenschappen
Alzheimer Disease (AD) is the predominant cause of dementia. AD is an incurable disease characterized by a progressive decline of memory and cognitive capabilities. Molecular genetic investigation of patients presenting with early-onset AD (EOAD) identified highly pathogenic mutations in the APP, PSEN1, and PSEN2 genes. Additionally, over twenty-five genetic loci have been associated with late-onset AD (LOAD) susceptibility, mostly identified through genome-wide association studies (GWAS).
The central aim of this doctoral thesis was the identification of functional genetic variants that underlie the identified risk loci and the mechanisms through which genetic variants effectuate susceptibility of AD at the level of the transcriptome.
To achieve this goal we first investigated the presence of pathogenic variants in the sortilin-related receptor 1 (SORL1) gene. SORL1 is a neuronal sorting receptor that interacts directly with APP to reduce amyloid-β generation. We performed targeted massive parallel resequencing of SORL1 in a large-scale European EOAD cohort. We identified an increased burden of rare coding variants in EOAD patients. While missense mutations were identified in patients as well as in control individuals, we observed that variants resulting in a premature termination codon were identified exclusively in patients.
In addition, we investigated the contribution of genetic variability in the TANK-binding kinase 1 (TBK1) gene to EOAD. Loss-of-function mutations in TBK1 have recently been identified as an important cause of frontotemporal dementia. We performed massive parallel re-sequencing of TBK1 in European EOAD patients. We identified one proven pathogenic TBK1 mutation identified in a clinically diagnosed EOAD patient with a positive family history of ALS. We further observed a trend towards association for a common coding variant in TBK1, which was also associated with decreased TBK1 mRNA expression.
Targeted sequencing of risk genes indicated altered expression of gene products as a common mechanism of pathogenic variants. To investigate gene expression deregulation on a genome-wide scale, we performed RNA sequencing in frontal cortex and hippocampal tissue in AD patients and control individuals. We identified region-specific and shared gene expression and co-expression patterns in AD brain, indicative of impairment of synaptic transmission in both brain regions. RNA sequencing in peripheral blood-derived lymphoblast cell lines in AD patients and control individuals revealed conserved differential expression patterns for several genes, substantiating that expression deregulation in brain tissue is not purely reflective of altered tissue composition in neurodegeneration.
Through identification of gene expression regulation of genetic variants associated with AD, and expression patterns in multiple tissues in AD, this thesis contributed to the understanding of the impact of genetic factors on the AD transcriptome.