Investigating the role of CLU PICALM and CR1 in Alzheimer's disease

Lord, Jenny (2014) Investigating the role of CLU PICALM and CR1 in Alzheimer's disease. PhD thesis, University of Nottingham.

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In 2009, two large genome wide association studies (GWAS) found associations between common single nucleotide polymorphisms (SNPs) at three loci (CLU, PICALM and CR1) and Alzheimer’s disease (AD) risk. The causal variants underlying these associations and how these impact on AD susceptibility remain unclear. Target enrichment and next generation sequencing (NGS) were used to completely resequence the three associated loci in 96 AD patients in an attempt to uncover potentially causative and rare variants that may explain the observed association signals. A pipeline was developed for the handling of pooled NGS data following a comparison of several different combinations of programs. 33 exonic SNPs were found within the three genes, along with over 1000 non-coding variants. To identify the variants most likely to be affecting AD risk, a two pronged approach was adopted. The variants were imputed in a large case-control cohort (2067 cases, 7376 controls) to test for association with AD, and the likely functional consequences of the variants were assessed using in silico resources. Several of the analysed variants showed suggestive or significant association with AD in the imputed data, and/or were predicted to have consequences on the function or regulation of the genes, suggesting avenues for future research in AD genetics. The whole method of pooled, targeted NGS and prioritisation using imputed data for association testing and in silico resources for functional analysis represents a new strategy for tracking down the illusive causation of GWAS signals.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Morgan, K.
Kalsheker, N.
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: 14273
Depositing User: EP, Services
Date Deposited: 16 Oct 2014 13:11
Last Modified: 16 Dec 2017 03:44

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