Investigating the genetics of sporadic early-onset Alzheimer’s disease using a customised genotyping chip

Barber, Imelda Stacey (2016) Investigating the genetics of sporadic early-onset Alzheimer’s disease using a customised genotyping chip. PhD thesis, University of Nottingham.

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Alzheimer’s disease (AD) is the commonest form of dementia and is characterised with neuropathological hallmarks such as aggregated amyloid plaques and hyper-phosphorylated tau protein. One type of AD is autosomal dominant AD (ADAD) which is caused by highly penetrant variants in one of three genes (APP, PSEN1 and PSEN2), other cases of AD are described as sporadic and can have a late onset of disease symptoms (> 65 years of age) or early onset (≤ 65 years or age). Late-onset Alzheimer’s disease (LOAD) is estimated to be 70% heritable and is common. Conversely sporadic early-onset Alzheimer’s disease (sEOAD) is estimated to 90% heritable but is relatively rare. The difference in prevalence between the two types of AD has resulted in genome wide association studies focusing on LOAD with sEOAD receiving little attention. Here we use an Illumina human exome genotyping chip customised with neurodegenerative markers (NeuroX) to genotype the coding region of sEOAD samples in a hope to elucidate the genetic aetiology of sEOAD.

Sanger sequencing exons 16 and 17 of APP was conducted in a sEOAD cohort (n=451) to screen for variants known to cause ADAD; 9% (n=4) of the cohort were heterozygous for known causative variants and where subsequently removed from the sEOAD NeuroX genotyping data before analyses. Screening also highlighted an intronic 6bp deletion downstream of exon 17 in APP with a non-significant increased minor allele frequency (MAF) in sEOAD, however it did not appear to influence splicing of exon 17. Screening the sEOAD cohort for other variants known to cause neurodegenerative disease was conducted using the NeuroX genotyping data (n=408) which identified two samples with variants in PARK2, these variants are thought to contribute susceptibility to Parkinson’s disease (PD) suggesting these variants might elicit risk for multiple diseases. A further study with increased power would ascertain if the 6bp deletion and PARK2 variants are associated with sEOAD.

Statistical analyses of the sEOAD NeuroX genotypes highlighted many variants, genes and pathways that could be contributing to susceptibility to disease; however no tests reached significance after adjusting for multiple testing. The genes most associated (PDZK1, DCLK3, SLC33A1 and BLOC1S2) appear to be biologically relevant and would be ideal candidates for further study. Additionally, just under half of the variants that are significant associated with LOAD were genotyped on the NeuroX and two of these were significantly associated with sEOAD after correcting for multiple testing (rs3851179 and rs3764650). The genotypes of all the variants highlighted would need to be verified before their functionalities were investigated further.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Morgan, K.
Chappell, S.
Keywords: Alzheimer's disease, Genetic aetiology, Neurodegenerative markers, Genetic markers
Subjects: R Medicine > RC Internal medicine
W Medicine and related subjects (NLM Classification) > WT Geriatrics. Chronic disease
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID: 37409
Depositing User: Barber, Imelda
Date Deposited: 15 Dec 2016 06:40
Last Modified: 08 Feb 2019 08:17

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