In partial fulfillment of the requirements for the degree of
Doctor of Philosophy in Bioinformatics
in the School of Biological Sciences
Courtney Alexandra Astore
Defends her thesis:
Genetic influences of fatty acid metabolism and ancestral origins on disease
Thursday, May 18th, 2023
11:00 AM
Krone Engineered Biosystems Building (EBB), CHOA Seminar Room
Zoom Link = https://gatech.zoom.us/j/97383649688
Thesis Advisor:
Dr. Greg Gibson
School of Biological Sciences
Georgia Institute of Technology
Committee Members:
Dr. I. King Jordan
School of Biological Sciences
Georgia Institute of Technology
Dr. Joseph Lachance
School of Biological Sciences
Georgia Institute of Technology
Dr. John F. McDonald
School of Biological Sciences
Georgia Institute of Technology
Dr. Christopher R. Bauer
Translational Genomics
BioMarin Pharmaceuticals
Abstract:
Although there have been extensive efforts to study the influence of environmental factors and their interactions with various diseases, the contribution of metabolomic imbalances in the development and pathogenesis of disease is still not fully understood. Furthermore, despite numerous attempts to replicate the findings of genome-wide association studies (GWAS) in diverse populations, little progress has been made in replicating the associations of rare variants with complex diseases. The objective of this thesis is to leverage a combination of biobank-level phenotype and genetic data to investigate the effects of metabolites as well as explore the ancestral origins of rare variants in inflammatory bowel disease (IBD) and in other disease areas. Thus, the three chapters of this thesis investigate the roles of two main areas in human diseases: (1) fatty-acid metabolism, and (2) admixture and rare variants.
The first study investigates the causal association between circulating metabolites and IBD. This study leverages the use of Mendelian Randomization (MR), a method that uses significant genetic variants from the GWAS of the exposure trait as instrumental variables to assess the causal relationship between a modifiable exposure and an outcome. In this case, we assessed over 200 metabolites and evaluated their relationship to IBD via MR. Omega-3 fatty acids were found to be one of the most significant protective associations with IBD, which was replicated in three independent GWAS. The second study is an extension of the first study, which further evaluates the disease architectures of 3 polyunsaturated fatty acids (PUFAs), omega-3 fatty acids, omega-6 fatty acids, and docosahexaenoic acid (DHA). The objective of this study is to demonstrate integrative PheWAS approaches using the metabolite levels and their polygenic scores to assess the association between the three PUFAs and over 1,300 disease endpoints. Using the metabolite-disease associations with concordant significant evidence from both approaches, we applied MR to assess causality. Protective associations with concordant evidence from all three PUFAs were identified.
The last study assesses the role of admixture on the rare variant contribution to IBD. In this chapter we investigated the impact of 25 rare, European ascertained, Crohn’s disease (CD) variants identified by Sazonovs et.al. on IBD in African American whole genome sequencing data. Our findings showed a consistent four-to-five-fold reduction in allele frequency in African Americans when compared to European. Further, phasing on the WGS data confirmed that the CD risk alleles discovered in Europeans contributes to the risk in African Americans due to admixture. Additionally, we found that 45 rare variants discovered by a meta-analysis of UK Biobank and FinnGen spanning ten disease classes from Sun et.al. are also mostly present due to admixture in the African American cohort. These results highlight the importance of conducting whole exome and genome sequencing studies on large, diverse cohorts to gain a better understanding on the role of rare variants in disease and promote equitable research practices.