Alzheimer’s disease (AD) is a complex neurodegenerative disease characterized by progressive memory loss and caused by a combination of genetic, environmental, and lifestyle factors. AD susceptibility is highly heritable at 58-79%, but only about one third of the AD genetic component is accounted for by common variants discovered through genome-wide association studies (GWAS). Rare variants may contribute to some of the unexplained heritability of AD and have been demonstrated to contribute to large gene expression changes across tissues, but conventional analytical approaches pose challenges because of low statistical power even for large sample sizes. Recent studies have demonstrated by expression quantitative trait locus (eQTL) analysis that changes in gene expression could play a key role in the pathogenesis of AD. However, regulation of gene expression has been shown to be context-specific (e.g., tissue and cell-types), motivating a context dependent approach to achieve more precise and statistically significant associations. To address these issues, I applied a strategy to identify new AD risk or protective rare variants by examining mutations occurring only in cases or only controls, observing that different mutations in the same gene or variable dose of a mutation may result in distinct dementias. I also evaluated the impact of rare variation on expression at the gene and gene pathway levels in blood and brain tissue, further strengthening the rare variant findings with functional evidence and finding evidence for a large immune and inflammatory component to AD. Lastly, I identified cell-type specific eQTLs in blood and brain tissue to explain underlying genetic associations of common variants in AD, and also discovered additional evidence for the role of myeloid cells in AD risk and potential novel blood and brain AD biomarkers. Collectively, these findings further explain the genetic basis of AD risk and provide insight about mechanisms leading to this disorder. / 2022-01-21T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/41911 |
| Date | 21 January 2021 |
| Creators | Patel, Devanshi |
| Contributors | Farrer, Lindsay A., Zhang, Xiaoling |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution-NonCommercial-ShareAlike 4.0 International, http://creativecommons.org/licenses/by-nc-sa/4.0/ |
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