Bioinformatics Approaches for Investigating Missing Heritability in Complex Traits
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Authors
Choi, Jihoon
Date
Type
thesis
Language
eng
Keyword
Bioinformatics , Genomics , Genetics , Omics , Computational Biology , Missing Heritability , Machine Learning , Omics Integration , Gene-Environment Interaction , Gene-Gene Interaction , Network Analysis , Variant Annotation , Linkage Disequilibrium , Asthma , Recurrent Wheeze , Ovarian Cancer , Chemoresistance , Pharmacogenomics , Computational Genomics , Complex Trait
Alternative Title
Abstract
Advancements in high-throughput technologies and high-performance computing have enabled the discovery of tens of thousands of genetic associations for complex traits and diseases. However, these associations explain only part of the heritability, defined as the portion of the trait variability that is accounted for by genetic factors. The overarching goal of my dissertation is to investigate the missing heritability in order to improve our understanding of the underlying genomic factors. First, we tested the hypothesis that many of the associated markers for complex traits are non-causal but are in linkage disequilibrium (LD) with causal variants. We identified 27 potentially functional variants in LD with previously associated markers for drug response outcomes, which could account in part for the missing heritability of pharmacogenomic traits. Next, we examined the main effects of genetic variations as well as interaction effects with environmental exposures in determining risk of complex diseases. In our study of childhood asthma, we computed the genetic risk score (GRS) by integrating the weighed effects of multiple genetic variants and determined that early-life modifiable exposures interact with genetic risk to determine respiratory outcomes. Finally, we applied a weighted network model and machine learning algorithm to investigate biological networks associated with chemotherapy response among ovarian cancer patients and identified potentially regulatory variants (expression quantitative loci: eQTL) associated with gene expression. In summary, my thesis work demonstrates that the missing heritability of complex traits may be explained in part by accounting for polygenic effects, gene-gene interactions, gene-environment interactions, linkage disequilibrium, and integrative analysis of 'omics datasets.
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Queen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canada
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Attribution-NonCommercial-NoDerivs 3.0 United States
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Attribution-NonCommercial-NoDerivs 3.0 United States