Dissertation
A computational investigation of Doberman dilated cardiomyopathy
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2023
DOI: 10.25820/etd.007219
Abstract
This thesis concerns the development and pathology of dilated cardiomyopathy(DCM) in Doberman Pinschers, a population known for its increased
susceptibility relative to other domestic dogs. We begin with a broad discussion of cardiomyopathies as a family of diseases before narrowing our
focus to DCM in particular. We present our analysis in two parts. First, we apply statistical models and data analysis methods to detect associations
between genetic mutations and disease status. Then, utilizing dynamical systems modeling and numerical methods, we study one such association
reported in the literature.
Genome-wide association studies (GWAS) are useful for detecting candidate genes associated with complex diseases in a population. We conduct a GWAS leveraging a database of genetic profiles obtained through collaboration with the Doberman Diversity Project. We cover common association models such as linear and logistic regression. But because these investigations require substantial statistical power and are prone to type I and type II errors, we also discuss alternative mixed effects models. These incorporate genetic variance as stochastic effects, increasing the strength of the corresponding association study while mitigating potential errors. Our analyses include thorough reports of data collection methodologies, data cleaning and quality control, as well as the association tests themselves.
Following our search for candidate genes, we develop a model describing a previously reported association. In 2012, a GWAS detected an association between a mutation in the gene encoding for the enzyme pyruvate dehydrogenase kinase 4 (PDK4) and DCM development in Doberman Pinschers. The pyruvate dehydrogenase complex (PDC) consists of three enzymes which together convert pyruvate, a product of glycolysis, to acetyl-CoA. PDK4 inhibits this conversion, and is thought to act as a switch between pyruvate decarboxylation and fatty acid oxidation. We present a preliminary model describing the interaction between PDK4 and the PDC. We observe a separation of timescales and explore the fast-slow dynamics of the system. Steady-state analysis suggests PDK4 could serve to maintain minimum pyruvate levels during starvation, rather than act as a metabolic switch between the two pathways.
Details
- Title: Subtitle
- A computational investigation of Doberman dilated cardiomyopathy
- Creators
- Alex Polenberg
- Contributors
- Colleen C Mitchell (Advisor)Bruce Ayati (Committee Member)Isabel K Darcy (Committee Member)Chad Eric Grueter (Committee Member)Yangyang Wang (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Applied Mathematical and Computational Sciences
- Date degree season
- Spring 2023
- DOI
- 10.25820/etd.007219
- Publisher
- University of Iowa
- Number of pages
- xii, 95 pages
- Copyright
- Copyright 2023 Alex Polenberg
- Comment
This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: https://www.lib.uiowa.edu/sc/contact/.
- Language
- English
- Date submitted
- 04/24/2023
- Date approved
- 05/09/2023
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 90-95).
- Public Abstract (ETD)
Doberman Pinschers are famous for their intelligence and loyalty. Unfortunately, they are also known for their susceptibility to a specific form of heart disease: dilated cardiomyopathy (DCM). Genetics play a key role in its development; as such, we have two goals in this thesis. First, we aim to identify potential genes associated with Doberman DCM. Then we study one such association reported in the literature using dynamical systems modeling.
We begin with a genome-wide association study (GWAS) using genetic data obtained through collaboration with the Doberman Diversity Project. We present our sampling methodologies in detail; in addition, we present each piece of the data cleaning pipeline before discussing the association tests themselves. After that, we turn our attention to a previously reported association. Specifically, a 2012 GWAS detected an association between Doberman DCM and a mutation in the gene encoding for the enzyme pyruvate dehydrogenase kinase 4 (PDK4). We present a preliminary model describing the behavior of PDK4, explore various aspects of the resulting system, and discuss its biological relevance.
- Academic Unit
- Craniofacial Anomalies Research Center; Interdisciplinary Graduate Program in Applied Mathematical & Computational Sciences
- Record Identifier
- 9984425389802771
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