Indiana University-Purdue University Indianapolis (IUPUI) / Determining an individual’s genetic susceptibility in complex diseases like Alzheimer’s
disease (AD) is challenging as multiple variants each contribute a small portion of the
overall risk. Polygenic Risk Scores (PRS) are a mathematical construct or composite that
aggregates the small effects of multiple variants into a single score. Potential applications
of PRS include risk stratification, biomarker discovery and increased prognostic accuracy.
A systematic review demonstrated that methodological refinement of PRS is an active
research area, mostly focused on large case-control genome-wide association studies
(GWAS). In AD, where there is considerable phenotypic and genetic heterogeneity, we
hypothesized that PRS based on endophenotypes, and pathway-relevant genetic
information would be particularly informative. In the first study, data from the NIA
Alzheimer’s Disease Neuroimaging Initiative (ADNI) was used to develop
endophenotype-based PRS based on amyloid (A), tau (T), neurodegeneration (N) and
cerebrovascular (V) biomarkers, as well as an overall/combined endophenotype-PRS.
Results indicated that combined phenotype-PRS predicted neurodegeneration biomarkers
and overall AD risk. By contrast, amyloid and tau-PRSs were strongly linked to the
corresponding biomarkers. Finally, extrinsic significance of the PRS approach was
demonstrated by application of AD biological pathway-informed PRS to prediction of
cognitive changes among older women with breast cancer (BC). Results from PRS analysis
of the multicenter Thinking and Living with Cancer (TLC) study indicated that older BC
patients with high AD genetic susceptibility within the immune-response and endocytosis pathways have worse cognition following chemotherapy±hormonal therapy rather than
hormonal-only therapy. In conclusion, PRSs based on biomarker- or pathway- specific
genetic information may provide mechanistic insights beyond disease susceptibility,
supporting development of precision medicine with potential application to AD and other
age-associated cognitive disorders.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/29299 |
| Date | 05 1900 |
| Creators | Chasioti, Danai |
| Contributors | Yan, Jingwen, Saykin, Andrew J., Nho, Kwangsik, Risacher, Shannon L., Wu, Huanmei |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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