ORCID
http://orcid.org/0000-0001-9324-1927
Date of Award
Spring 5-15-2021
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Precision medicine defines both health and disease in terms of high dimensional data. In my thesis work, I apply current knowledge and tools of precision medicine to better understand the etiopathogenesis of neurodegenerative diseases (NDs).
Genome-wide association studies (GWAS) have demonstrated that genetic susceptibility for NDs and other diseases is mediated by many common genetic variants of modest effect size which contribute to disease risk in a polygenic or even omnigenic manner. These complex genetics render prioritizing genes to better understand the disease and potentially identify therapeutic targets, challenging. In the first half of this thesis, I address this challenge by leveraging the comorbidity between Parkinson disease (PD) and cutaneous melanoma (melanoma). I apply modern linkage disequilibrium-informed methods to the currently largest available GWAS summary statistics for PD and melanoma to identify shared genetic architecture between these diseases and prioritize genes whose inferred expression is commonly impacted by disease-associated genetic variants for downstream functional analyses.
Comparing gene expression in disease-relevant tissues can directly identify disease-associated genes. The majority of such transcriptomic studies in NDs have focused on the linear, protein-coding transcriptome. However, non-messenger RNAs, such as circular RNAs (circRNAs), have important regulatory functions under both physiologic and pathologic conditions. In the second half of this thesis, I analyze circular RNA differential expression in human brain tissues donated by individuals with and without neuropathologically-diagnosed Alzheimer disease (AD). I identify significant associations with circRNAs and AD and provide evidence for expression changes occurring before the onset of clinical dementia symptoms. I also demonstrate that AD-associated circRNAs co-express with known AD genes and pathways and yield strong predictive ability for AD case status, even in the absence of demographic or genetic risk factor data. Together, my results support future studies exploring circRNAs as biomarkers for AD and for the potential roles in AD pathogenesis.
In conclusion, my dissertation work demonstrates the utility of applying the methods of precision medicine to better understand the etiopathogenesis of NDs. My analysis approaches can be applied to other diseases and complex traits as more genomic and transcriptomic data become available.
Language
English (en)
Chair and Committee
Carlos Cruchaga Brad Racette
Committee Members
Nancy L. Saccone, John E. McCarthy, Christina A. Gurnett, Timothy Miller,
Recommended Citation
Dube, Umber, "Polygenic and Transcriptomic Studies in Neurodegeneration: Towards More Precise Medicine." (2021). Arts & Sciences Electronic Theses and Dissertations. 2410.
https://openscholarship.wustl.edu/art_sci_etds/2410