Genome-wide copy number variation analysis in early onset Alzheimer's disease
Year: 2011
Type: dissertation
Study design: Observational Study
Abstract: Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of senile dementia. By the year 2050, AD prevalence is projected to affect a staggering 15 million in the US and 80 million worldwide, making discovery of therapeutic interventions imperative. Family history is the second major risk factor in AD following age. Although close to 700 different genes have been investigated in AD to date, fully penetrant mutations in three genes: APP, PSEN1 and PSEN2 known to cause early-onset familial AD (EOFAD), and a common e4 allele in APOE increasing risk in sporadic or late onset form of AD (LOAD), remain the only established AD genetic factors; altogether explaining just about 50% of the variance. Rationale and Aim: A Majority of the published reports in AD genetics are based on nucleotide level changes, while role of large genomic structural rearrangementssuch as, copy number variations (CNVs), are not comprehensively investigated - APP locus duplication remains the only pathogenic CNV reported to date. With an estimated genomic coverage of over ten times that of single nucleotide polymorphisms (SNPs), CNVs make significant contribution to genotypic and phenotypic variation, consequently underlying pathogenesis of various diseases. The specific aim of the project is to perform genome-wide CNV analysis in AD afflicted families to identify presence of pathogenic CNVs, if any. Approach: Genetic studies in EOFAD pedigrees have been most fruitful in revealing rare mutations, which also contributed significantly to the current understanding of AD pathogenesis. On the other hand, the complex and heterogeneous nature of genetics of LOAD have been hard to unravel. Therefore, this study is limited to analysis of large (>100 Kb), rare and fully penetrant CNVs in early-onset pedigree samples (261 families and 1015 subjects). Results: In addition to confirming APP duplication in two previously known families, our results revealed nine rare and novel CNVs segregating with EOFAD. The CNVs encompass genes, ERMP1, CRMP1, CHMP2B, VLDLR, A2BP1, and EPHA6, to name a few, associated with various neuronal pathways and brain disorders. To our knowledge, this is the first study reporting rare generich CNVs in EOFAD.
DOI: 10.17918/etd-3641
Institutions: University of Dhaka, Drexel University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4205761366