Author ORCID Identifier

Defense Date


Document Type


Degree Name

Doctor of Philosophy


Human and Molecular Genetics

First Advisor

Timothy York, PhD

Second Advisor

Roxann Roberson-Nay, PhD


Epigenetic mechanisms have been hypothesized to modify gene expression (GE) in response to both genetic variation and environmental exposures, ultimately contributing to the development of complex traits. Epigenome-wide association studies (EWAS) aim to test the theory that marks of DNA methylation (DNAm) have downstream consequences that result in the development of complex diseases. Although these methods have been successful in identifying DNAm patterns in complex traits, specific molecular mechanisms involved in the etiology of complex diseases remain unidentified. This knowledge gap does not originate from a lack of DNAm-trait associations, but rather stems from study design issues that affect the interpretability of EWAS results. This study integrated concomitant DNAm and GE measurements in two cohorts to improve understanding of epigenetic functional mechanisms involved in disease. DNAm showed significant relationships with both proximal and distal GE across the genome. CpG sites associated with GE in cis were enriched in areas of transcription factor binding and areas of intermediate to low CpG density, while trans CpGs were preferentially located within enhancer regions. These results highlight issues with restricting DNAm-transcript annotations to small genomic intervals and question the validity of assuming a canonical cis DNAm-GE pathway when investigating epigenetic mechanisms. As DNAm-trait associations could serve as biological predictors of disease, this study also explored the generalizability of DNAm-based biomarkers in predicting risk for adverse pregnancy outcomes. Results indicate that the predictive ability of these biomarkers may differ by genetic ancestry and technical factors, which necessitate further investigation before universal application.


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Available for download on Saturday, September 27, 2025