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Vanderbilt University
1.
D'Aoust, Laura Nicole.
Examination of Candidate Exonic Variants that Confer Susceptibility to Alzheimer Disease in the Amish.
Degree: PhD, Human Genetics, 2015, Vanderbilt University
URL: http://hdl.handle.net/1803/10861 
► Alzheimer disease (AD) is the most common cause of dementia. As with many complex diseases, the identified variants do not explain the total expected genetic…
(more)
▼ Alzheimer disease (AD) is the most common cause of dementia. As with many complex diseases, the identified variants do not explain the total expected genetic risk that is based on heritability estimates for AD. Isolated founder populations, such as the Amish, are advantageous for genetic studies as they overcome limitations associated with complex population studies. Amish AD cases harbored a significantly higher burden of the known risk alleles compared to Amish cognitively normal controls, but a significantly lower burden when compared to cases from a cohort of unrelated individuals. These results suggest that known loci explain some of the genetic effects and that there may be different underlying genetic architectures between the two populations. Whole-exome sequencing of a selected subset of the overall study population was used as a screening tool to identify variants located in the regions of the genome that are most likely to contribute risk. By then genotyping the top candidate variants from the known AD genes and implicated linkage regions from previous studies in the full data set, new associations could be confirmed. The most significant result (p = 0.0012) was for rs73938538, a synonymous variant in LAMA1 within the previously identified linkage peak on chromosome 18, but this association did not generalize when tested in a dataset of unrelated individuals. These results indicate that exonic variation in a majority of previously associated LOAD genes, and regions implicated by previous linkage studies, does not contribute to risk for LOAD in the Amish.
Advisors/Committee Members: Paul Newhouse (committee member), Tricia Thornton-Wells (committee member), Jonathan L Haines (committee member), Bingshan Li (committee member), Dana Crawford (Committee Chair).
Subjects/Keywords: Alzheimer; family-based study; genetics
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APA (6th Edition):
D'Aoust, L. N. (2015). Examination of Candidate Exonic Variants that Confer Susceptibility to Alzheimer Disease in the Amish. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10861
Chicago Manual of Style (16th Edition):
D'Aoust, Laura Nicole. “Examination of Candidate Exonic Variants that Confer Susceptibility to Alzheimer Disease in the Amish.” 2015. Doctoral Dissertation, Vanderbilt University. Accessed April 17, 2021.
http://hdl.handle.net/1803/10861.
MLA Handbook (7th Edition):
D'Aoust, Laura Nicole. “Examination of Candidate Exonic Variants that Confer Susceptibility to Alzheimer Disease in the Amish.” 2015. Web. 17 Apr 2021.
Vancouver:
D'Aoust LN. Examination of Candidate Exonic Variants that Confer Susceptibility to Alzheimer Disease in the Amish. [Internet] [Doctoral dissertation]. Vanderbilt University; 2015. [cited 2021 Apr 17].
Available from: http://hdl.handle.net/1803/10861.
Council of Science Editors:
D'Aoust LN. Examination of Candidate Exonic Variants that Confer Susceptibility to Alzheimer Disease in the Amish. [Doctoral Dissertation]. Vanderbilt University; 2015. Available from: http://hdl.handle.net/1803/10861
Vanderbilt University
2.
Dumitrescu, Logan Caneel.
Identificatiion and Characterization of Genetic Variants Associated with Lipid and Lipoprotein Levels.
Degree: PhD, Human Genetics, 2011, Vanderbilt University
URL: http://hdl.handle.net/1803/11282
► Low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels are well known independent risk factors for cardiovascular disease. Other lipoproteins, such as…
(more)
▼ Low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels are well known independent risk factors for cardiovascular disease. Other lipoproteins, such as Lp(a), are also emerging, independent risk factors as increasing epidemiologic evidence suggests. Lipid-associated single-nucleotide polymorphisms (SNPs) are being discovered in genome-wide association studies (GWAS) in samples of European descent, but little data exist in other populations. Therefore, there is a strong need to characterize the effect sizes and allele frequencies of these GWAS-identified variants in a diverse, population-based cohort. Also, despite the ever-growing number of loci detected by GWAS, the proportion of trait variation explained is collectively small. To investigate this missing heritability, it is important to continue to identify novel variants that are associated with lipid levels and to explore gene-environment interactions, which may also contribute to trait variation.
The primary objective of this work was to identify and characterize common genetic variants that explain a proportion of the inter-individual variability in lipids levels, including LDL-C, HDL-C, TG, and Lp(a) levels. To achieve this goal, I selected a set of SNPs associated with lipid levels from the literature and demonstrated that the majority of associations replicate and generalize in a diverse, independent cohort. An additional GWAS of children was used to discover a novel variants associated with LDL-C, HDL-C, and TG. I also performed a candidate gene study and determined that common variants in LPA were associated with Lp(a) levels. Lastly, I identified several environmental modifiers of replicated variants associated with LDL-C, HDL-C, and TG.
Advisors/Committee Members: Dana Crawford (committee member), Jonathan Haines (committee member), Mary Relling (committee member), Jay Fowke (committee member), Marylyn Ritchie (Committee Chair).
Subjects/Keywords: genetics; epidemiology; gwas; candidate gene study; lipids; lipoproteins; cardiovascular disease
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APA (6th Edition):
Dumitrescu, L. C. (2011). Identificatiion and Characterization of Genetic Variants Associated with Lipid and Lipoprotein Levels. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/11282
Chicago Manual of Style (16th Edition):
Dumitrescu, Logan Caneel. “Identificatiion and Characterization of Genetic Variants Associated with Lipid and Lipoprotein Levels.” 2011. Doctoral Dissertation, Vanderbilt University. Accessed April 17, 2021.
http://hdl.handle.net/1803/11282.
MLA Handbook (7th Edition):
Dumitrescu, Logan Caneel. “Identificatiion and Characterization of Genetic Variants Associated with Lipid and Lipoprotein Levels.” 2011. Web. 17 Apr 2021.
Vancouver:
Dumitrescu LC. Identificatiion and Characterization of Genetic Variants Associated with Lipid and Lipoprotein Levels. [Internet] [Doctoral dissertation]. Vanderbilt University; 2011. [cited 2021 Apr 17].
Available from: http://hdl.handle.net/1803/11282.
Council of Science Editors:
Dumitrescu LC. Identificatiion and Characterization of Genetic Variants Associated with Lipid and Lipoprotein Levels. [Doctoral Dissertation]. Vanderbilt University; 2011. Available from: http://hdl.handle.net/1803/11282
Vanderbilt University
3.
Edwards, Todd L.
An Extension to and Application of the Multifactor Dimensionality Reduction Pedigree Disequilibrium Test.
Degree: PhD, Human Genetics, 2008, Vanderbilt University
URL: http://hdl.handle.net/1803/10658
► As the field of genetics explores beyond mapping single-site disease susceptibility loci, epistasis between genes is being considered in disease models. These hypotheses present new…
(more)
▼ As the field of genetics explores beyond mapping single-site disease susceptibility loci, epistasis between genes is being considered in disease models. These hypotheses present new problems for investigators as they search through ever more complex data structures. The dimensionality and size of a search space, the types and strengths of disease associations in data, and the quality of inference allowed given a result are all challenges when testing for putative epistatic disease models.
Method development to analyze family data for epistatic interactions is in a preliminary stage. The multifactor dimensionality reduction pedigree disequilibrium test (MDR-PDT) is one technique for assessing epistatic models in family data. The objective of this proposal is to refine, test, and apply this method to real data.
MDR-PDT is a method that implements the genoPDT statistic within the framework of the MDR algorithm. We hypothesize that at the conclusion of my aims, the MDR-PDT algorithm’s utility and power will be improved. In the following dissertation we developed a cross validation algorithm for pedigree data, and an omnibus model selection method. We also implemented an extension to MDR-PDT that includes a likelihood ratio test for the statistical significance of an interaction found by the MDR-PDT search using logistic regression. Finally, MDR-PDT was applied to Alzheimer’s candidate gene datasets and revealed a multilocus model involving several genes that are functional candidates.
Advisors/Committee Members: Dana Crawford (committee member), Eden Martin (committee member), Charles Matthews (committee member), Marylyn Ritchie (committee member), Jonathan Haines (Committee Chair).
Subjects/Keywords: Association; Epistasis; Interaction; Genetics; Epidemiology
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APA (6th Edition):
Edwards, T. L. (2008). An Extension to and Application of the Multifactor Dimensionality Reduction Pedigree Disequilibrium Test. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10658
Chicago Manual of Style (16th Edition):
Edwards, Todd L. “An Extension to and Application of the Multifactor Dimensionality Reduction Pedigree Disequilibrium Test.” 2008. Doctoral Dissertation, Vanderbilt University. Accessed April 17, 2021.
http://hdl.handle.net/1803/10658.
MLA Handbook (7th Edition):
Edwards, Todd L. “An Extension to and Application of the Multifactor Dimensionality Reduction Pedigree Disequilibrium Test.” 2008. Web. 17 Apr 2021.
Vancouver:
Edwards TL. An Extension to and Application of the Multifactor Dimensionality Reduction Pedigree Disequilibrium Test. [Internet] [Doctoral dissertation]. Vanderbilt University; 2008. [cited 2021 Apr 17].
Available from: http://hdl.handle.net/1803/10658.
Council of Science Editors:
Edwards TL. An Extension to and Application of the Multifactor Dimensionality Reduction Pedigree Disequilibrium Test. [Doctoral Dissertation]. Vanderbilt University; 2008. Available from: http://hdl.handle.net/1803/10658
Vanderbilt University
4.
Hollister, Brittany Marie.
Examining the Role of Socioeconomic Status on Blood Pressure in African Americans.
Degree: PhD, Human Genetics, 2017, Vanderbilt University
URL: http://hdl.handle.net/1803/13798
► Understanding the genetic and environmental factors contributing to blood pressure is an important step in elucidating the causes of hypertension, a disease of high blood…
(more)
▼ Understanding the genetic and environmental factors contributing to blood pressure is an important step in elucidating the causes of hypertension, a disease of high blood pressure. African Americans experience the highest burden of hypertension in the United States, however little is known about the genetic factors contributing to blood pressure in African Americans, despite a high estimated heritability. Furthermore, current large scale studies of genetic variants contributing to blood pressure in African Americans do not include socioeconomic status (SES) information, in spite of a strong association between SES and blood pressure. To examine the potential interactions between SES and genetic variants contributing to blood pressure, a hospital-based population with electronic health records was used. Prior to conducting genetic analysis, several algorithms were developed to extract SES information from electronic health records (EHR). These algorithms extracted occupation, retirement, education level, unemployment, homelessness, Medicaid, and uninsured status with high accuracy. With the extracted education information, interactions between genetic variants contributing to blood pressure in African Americans and education were examined. No statistically significant interactions were observed. Some novel statistically significant and suggestive associations between genetic variants and blood pressure were observed. One suggestive interaction between a genetic variant and education level affecting blood pressure was detected. These results indicate that exploring interactions between SES data extracted from EHRs and genetic variants is possible on a large scale.
Advisors/Committee Members: Todd Edwards (committee member), Derek Griffith (committee member), Dana Crawford (committee member), Amy Non (committee member), Melinda Aldrich (Committee Chair).
Subjects/Keywords: African Americans; genetic; socioeconomic status; blood pressure
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APA (6th Edition):
Hollister, B. M. (2017). Examining the Role of Socioeconomic Status on Blood Pressure in African Americans. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/13798
Chicago Manual of Style (16th Edition):
Hollister, Brittany Marie. “Examining the Role of Socioeconomic Status on Blood Pressure in African Americans.” 2017. Doctoral Dissertation, Vanderbilt University. Accessed April 17, 2021.
http://hdl.handle.net/1803/13798.
MLA Handbook (7th Edition):
Hollister, Brittany Marie. “Examining the Role of Socioeconomic Status on Blood Pressure in African Americans.” 2017. Web. 17 Apr 2021.
Vancouver:
Hollister BM. Examining the Role of Socioeconomic Status on Blood Pressure in African Americans. [Internet] [Doctoral dissertation]. Vanderbilt University; 2017. [cited 2021 Apr 17].
Available from: http://hdl.handle.net/1803/13798.
Council of Science Editors:
Hollister BM. Examining the Role of Socioeconomic Status on Blood Pressure in African Americans. [Doctoral Dissertation]. Vanderbilt University; 2017. Available from: http://hdl.handle.net/1803/13798
Vanderbilt University
5.
Jeff, Janina Maria.
Admixture mapping and subsequent finemapping suggests novel loci for type 2 diabetes in African Americans.
Degree: MS, Interdisciplinary Studies: Applied Statistics, 2012, Vanderbilt University
URL: http://hdl.handle.net/1803/15329
► Type 2 diabetes (T2D) is a complex metabolic disease that disproportionately affects African Americans. Obesity is a major risk factor for T2D, and it is…
(more)
▼ Type 2 diabetes (T2D) is a complex metabolic disease that disproportionately affects African Americans. Obesity is a major risk factor for T2D, and it is postulated that chronic inflammation possibly stemming from adipose tissue macrophages and T cells plays a key role. Genome-wide association studies (GWAS) have identified over 20 disease loci that contribute to T2D in European Americans but few studies have been performed in admixed populations.
We first performed a GWAS of 1,563 African Americans from the
Vanderbilt Genome-Electronic Records Project and Northwestern
University NUgene Project as part of the electronic Medical Records and Genomics (eMERGE) network. We successfully replicate an association in TCF7L2, previously identified by GWAS in our African American dataset. We were unable to identify novel associations at p<5.0x10-8 by GWAS. Admixture mapping disease loci in recently admixed populations is a powerful method used to identify disease loci in African Americans. Using admixture mapping, we sought to identify novel disease loci in the genome with T2D. Our admixture scan revealed multiple candidate genes with T2D, including TCIRG1, a T-cell immune regulator expressed in the pancreas and liver and not previously implicated in T2D. We performed a subsequent fine-mapping analysis to further assess the association with TCIRG1 and T2D in >5,000 African Americans. We successfully identified 13 independent associations in TCIRG1, CHKA, and ALDH3B1 genes on chromosome 11. Our results suggest a novel region on chromosome 11 identified by admixture mapping associated with T2D in African Americans and warrants additional replication and validation in this region.
Advisors/Committee Members: Jonathan Haines (committee member), Dana Crawford (committee member).
Subjects/Keywords: admixture mapping; statistics; human genetics; type 2 diabetes
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APA (6th Edition):
Jeff, J. M. (2012). Admixture mapping and subsequent finemapping suggests novel loci for type 2 diabetes in African Americans. (Thesis). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/15329
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Jeff, Janina Maria. “Admixture mapping and subsequent finemapping suggests novel loci for type 2 diabetes in African Americans.” 2012. Thesis, Vanderbilt University. Accessed April 17, 2021.
http://hdl.handle.net/1803/15329.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Jeff, Janina Maria. “Admixture mapping and subsequent finemapping suggests novel loci for type 2 diabetes in African Americans.” 2012. Web. 17 Apr 2021.
Vancouver:
Jeff JM. Admixture mapping and subsequent finemapping suggests novel loci for type 2 diabetes in African Americans. [Internet] [Thesis]. Vanderbilt University; 2012. [cited 2021 Apr 17].
Available from: http://hdl.handle.net/1803/15329.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Jeff JM. Admixture mapping and subsequent finemapping suggests novel loci for type 2 diabetes in African Americans. [Thesis]. Vanderbilt University; 2012. Available from: http://hdl.handle.net/1803/15329
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Vanderbilt University
6.
Jeff, Janina Maria.
The Genetics of Quantitative Traits Associated with Cardiovascular Disease in African Americans.
Degree: PhD, Human Genetics, 2012, Vanderbilt University
URL: http://hdl.handle.net/1803/10690
► Cardiovascular disease (CVD) is the leading cause of death in most developed countries. In addition to environmental risk factors, such as diet and physical activity,…
(more)
▼ Cardiovascular disease (CVD) is the leading cause of death in most developed countries. In addition to environmental risk factors, such as diet and physical activity, genetic risk factors contribute to the CVD risk. Risk of CVD is not uniformly distributed across populations, as African Americans and Hispanics have more risk factors for CVD compared with European Americans. The use of quantitative traits to identify genetic risk factors is a potentially more powerful, informative and uniform approach compared with the use of binary or qualitative traits (such as CVD case status).
My primary objective is to identify genetic risk factors associated with the regulation fibrinogen/hematological and electrocardiogram (ECG) traits in African Americans. Both fibrinogen/hematological and ECG traits are common clinical characteristics of CVD and have a strong genetic component. The primary objective of this work is to identify genetic risk factors associated with the regulation fibrinogen/hematological and electrocardiogram (ECG) traits in African Americans. Both fibrinogen/hematological and ECG traits are common clinical characteristics of CVD and have a strong genetic component. Using three approaches: candidate gene, genome-wide association studies (GWAS), and testing for genetic interactions (gene-gene and gene-environment); we identify novel and previously identified genetic associations with ECG traits and fibrinogen/hematological traits in African Americans and other global populations.
Advisors/Committee Members: Dan Roden (committee member), Alyssa Hasty (committee member), Dana Crawford (committee member), Marylyn Ritchie (Committee Chair), Scott Williams (Committee Chair).
Subjects/Keywords: electrocardiographic traits; fibrinogen; African Americans; quantitative traits
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APA (6th Edition):
Jeff, J. M. (2012). The Genetics of Quantitative Traits Associated with Cardiovascular Disease in African Americans. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10690
Chicago Manual of Style (16th Edition):
Jeff, Janina Maria. “The Genetics of Quantitative Traits Associated with Cardiovascular Disease in African Americans.” 2012. Doctoral Dissertation, Vanderbilt University. Accessed April 17, 2021.
http://hdl.handle.net/1803/10690.
MLA Handbook (7th Edition):
Jeff, Janina Maria. “The Genetics of Quantitative Traits Associated with Cardiovascular Disease in African Americans.” 2012. Web. 17 Apr 2021.
Vancouver:
Jeff JM. The Genetics of Quantitative Traits Associated with Cardiovascular Disease in African Americans. [Internet] [Doctoral dissertation]. Vanderbilt University; 2012. [cited 2021 Apr 17].
Available from: http://hdl.handle.net/1803/10690.
Council of Science Editors:
Jeff JM. The Genetics of Quantitative Traits Associated with Cardiovascular Disease in African Americans. [Doctoral Dissertation]. Vanderbilt University; 2012. Available from: http://hdl.handle.net/1803/10690
Vanderbilt University
7.
Koran, Mary Ellen Irene.
Imaging and Genetics of Two Amyloid Related Diseases: Alzheimer’s Disease and Down Syndrome.
Degree: PhD, Human Genetics, 2014, Vanderbilt University
URL: http://hdl.handle.net/1803/10539
► Alzheimer’s Disease is an irreversible, degenerative disease of the brain that accounts for a majority of dementia cases each year, in both the general population…
(more)
▼ Alzheimer’s Disease is an irreversible, degenerative disease of the brain that accounts for a majority of dementia cases each year, in both the general population and in patients with Down Syndrome. The advancement of in vivo imaging modalities that detect the neuropathologies associated with both Down Syndrome and Alzheimer’s Disease present new opportunities to explore these diseases in living human subjects. Imaging biomarkers not only permit earlier, more accurate patient diagnosis, but quantitative, neuropathology-based traits derived from imaging modalities offer increased power to detect associations with large-scale genetic data. This field of investigation has been termed “imaging genetics”. Imaging genetics studies aim to identify novel risk genes and elucidate gene function and novel mechanisms of disease pathology and etiology. In this dissertation, I have conducted imaging genetics studies of the neuropathologies of Alzheimer’s Disease and Down Syndrome in order to increase our understanding of the genetic etiology underlying these pathologies. Furthermore, new biomarkers of these pathologies are still needed. Thus, a magnetic resonance imaging sequence which has been shown to detect amyloid beta plaque in mice is explored in human studies in this dissertation. This work contributes novel findings to the body of research aimed at early identification of patients at risk of Alzheimer’s Disease.
Advisors/Committee Members: Chun Li (committee member), Tricia Thornton-Wells (committee member), Dana Crawford (committee member), Brian Welch (committee member), Jonathan Haines (Committee Chair).
Subjects/Keywords: imaging; genetics; amyloid; alzheimers; aging; down; downs; MRI; PET
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APA (6th Edition):
Koran, M. E. I. (2014). Imaging and Genetics of Two Amyloid Related Diseases: Alzheimer’s Disease and Down Syndrome. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10539
Chicago Manual of Style (16th Edition):
Koran, Mary Ellen Irene. “Imaging and Genetics of Two Amyloid Related Diseases: Alzheimer’s Disease and Down Syndrome.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed April 17, 2021.
http://hdl.handle.net/1803/10539.
MLA Handbook (7th Edition):
Koran, Mary Ellen Irene. “Imaging and Genetics of Two Amyloid Related Diseases: Alzheimer’s Disease and Down Syndrome.” 2014. Web. 17 Apr 2021.
Vancouver:
Koran MEI. Imaging and Genetics of Two Amyloid Related Diseases: Alzheimer’s Disease and Down Syndrome. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2021 Apr 17].
Available from: http://hdl.handle.net/1803/10539.
Council of Science Editors:
Koran MEI. Imaging and Genetics of Two Amyloid Related Diseases: Alzheimer’s Disease and Down Syndrome. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://hdl.handle.net/1803/10539
Vanderbilt University
8.
Turner, Stephen Dale.
Knowledge-Driven Genome-Wide Analysis of Multigenic Interactions Impacting HDL Cholesterol Level.
Degree: PhD, Human Genetics, 2010, Vanderbilt University
URL: http://hdl.handle.net/1803/15293
► Growing interest and burgeoning technology for discovering genetic mechanisms that influence disease processes have ushered in a flood of genetic association studies over the last…
(more)
▼ Growing interest and burgeoning technology for discovering genetic mechanisms that influence disease processes have ushered in a flood of genetic association studies over the last decade, yet little heritability in highly studied complex traits has been explained by genetic variation. Non-additive gene-gene interactions, which are not often explored, are thought to be one source of this "missing" heritability. I begin this dissertation with a review of study designs and analytical methods for genetic association studies. Next, I characterize and present a series of improvements in using grammatical evolution to train neural networks for discovering gene-gene interactions in disease gene association studies. I then present an analysis of cis-epistasis - nonadditive multi-SNP interactions that influence gene expression. Next, I present a cohesive set of quality control procedures to be used for genome-wide association studies. Finally, I conclude by presenting results from a knowledge-driven gene-gene interaction analysis of HDL level in two clinical practice-based population biobanks.
Advisors/Committee Members: Yu Shyr (committee member), Marylyn D. Ritchie (committee member), Jonathan Haines (committee member), Erik Boczko (committee member), Dana Crawford (Committee Chair).
Subjects/Keywords: Human genetics; bioinformatics; machine learning; neural networks; cardiovascular disease; complex disease
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APA (6th Edition):
Turner, S. D. (2010). Knowledge-Driven Genome-Wide Analysis of Multigenic Interactions Impacting HDL Cholesterol Level. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/15293
Chicago Manual of Style (16th Edition):
Turner, Stephen Dale. “Knowledge-Driven Genome-Wide Analysis of Multigenic Interactions Impacting HDL Cholesterol Level.” 2010. Doctoral Dissertation, Vanderbilt University. Accessed April 17, 2021.
http://hdl.handle.net/1803/15293.
MLA Handbook (7th Edition):
Turner, Stephen Dale. “Knowledge-Driven Genome-Wide Analysis of Multigenic Interactions Impacting HDL Cholesterol Level.” 2010. Web. 17 Apr 2021.
Vancouver:
Turner SD. Knowledge-Driven Genome-Wide Analysis of Multigenic Interactions Impacting HDL Cholesterol Level. [Internet] [Doctoral dissertation]. Vanderbilt University; 2010. [cited 2021 Apr 17].
Available from: http://hdl.handle.net/1803/15293.
Council of Science Editors:
Turner SD. Knowledge-Driven Genome-Wide Analysis of Multigenic Interactions Impacting HDL Cholesterol Level. [Doctoral Dissertation]. Vanderbilt University; 2010. Available from: http://hdl.handle.net/1803/15293
Vanderbilt University
9.
White, Marquitta Jonisse.
Genetics of Plasminogen Activator Inhibitor – 1: a potent biological effector of cardiovascular disease risk.
Degree: PhD, Human Genetics, 2014, Vanderbilt University
URL: http://hdl.handle.net/1803/14029
► Cardiovascular disease (CVD) is an inclusive term encompassing several disorders of the circulatory system that together account for the majority of global non-communicable disease (NCD)…
(more)
▼ Cardiovascular disease (CVD) is an inclusive term encompassing several disorders of the circulatory system that together account for the majority of global non-communicable disease (NCD) mortality. Major thrombotic events, due in part to impaired fibrinolysis, are a unifying characteristic of several CVDs. Plasminogen activator inhibitor-1 (PAI-1) is a major regulator of fibrinolysis, and PAI-1 levels associate with CVD susceptibility and severity in several populations. The main objectives of this dissertation were to evaluate the genetic impact of common single nucleotide polymorphisms (SNPs) on inter-individual variation in PAI-1 levels in a Ghanaian population, and present a novel method to identify candidate genes for prioritization in future studies. We discovered novel associations between single variants in the arylsulfatase b (ARSB), carboxypeptidase A2 (CPA2), and leukocyte receptor cluster member 9 (LENG9) and median PAI-1 levels. Quantile regression analyses directed at the upper quartile of the PAI-1 distribution was performed to uncover novel variants with significant impact on this clinically relevant portion of the PAI-1 distribution. Upper quartile regression analyses revealed significant associations between single variants in period circadian clock 3 (PER3), a discovery that supports previous evidence of the involvement of the circadian pathway in regulation of PAI-1 levels in Caucasian populations as well as model organisms. This finding suggests that the significance of the circadian pathway as a whole may be generalizable across populations, even though gene effects may be population specific. We present a novel approach; Multi-lOcus based selection of Candidate genes (MOCA), which incorporates multi-variant association signals into the prioritization of genes for further evaluation. MOCA identified four significantly associated loci; these loci included 28 novel candidate genes for PAI-1 levels. Each MOCA identified locus was located within previously identified CVD and/or PAI-1 related quantitative trait loci (QTL).
Advisors/Committee Members: Nancy J. Brown (committee member), melinda aldrich (committee member), Dana Crawford (committee member), Jason Moore (committee member), Scott M. Williams (committee member), Bingshan Li (Committee Chair).
Subjects/Keywords: population genetics; plasminogen activator inhibitor-1; cardiovascular disease
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APA (6th Edition):
White, M. J. (2014). Genetics of Plasminogen Activator Inhibitor – 1: a potent biological effector of cardiovascular disease risk. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14029
Chicago Manual of Style (16th Edition):
White, Marquitta Jonisse. “Genetics of Plasminogen Activator Inhibitor – 1: a potent biological effector of cardiovascular disease risk.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed April 17, 2021.
http://hdl.handle.net/1803/14029.
MLA Handbook (7th Edition):
White, Marquitta Jonisse. “Genetics of Plasminogen Activator Inhibitor – 1: a potent biological effector of cardiovascular disease risk.” 2014. Web. 17 Apr 2021.
Vancouver:
White MJ. Genetics of Plasminogen Activator Inhibitor – 1: a potent biological effector of cardiovascular disease risk. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2021 Apr 17].
Available from: http://hdl.handle.net/1803/14029.
Council of Science Editors:
White MJ. Genetics of Plasminogen Activator Inhibitor – 1: a potent biological effector of cardiovascular disease risk. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://hdl.handle.net/1803/14029
Vanderbilt University
10.
Zuvich, Rebecca Lynn.
Pathway Approach to Decoding Multiple Sclerosis.
Degree: PhD, Human Genetics, 2009, Vanderbilt University
URL: http://hdl.handle.net/1803/15066
► Multiple sclerosis (MS) is characterized as a neurodegenerative autoimmune disease. This clinically complex disease has provided great challenges for geneticists over the years. With the…
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▼ Multiple sclerosis (MS) is characterized as a neurodegenerative autoimmune disease. This clinically complex disease has provided great challenges for geneticists over the years. With the advent of genome-wide association studies (GWAS), the strong genetic component associated with MS is finally beginning to be characterized. One of the first discoveries to emerge in this new era was the association with rs6897932 in the interleukin-7 receptor alpha chain (IL7RA) gene. The goal of the work presented in this dissertation was to identify additional genes that increase one’s susceptibility to MS. Our studies involved examining genes in the extended biological pathway related to IL7RA to identify novel associations. Through this approach, we identified two additional novel gene regions that are likely associated with MS. These results help to further delineate the genetic architecture of MS and validate our pathway approach as an effective method to identify novel associations associated in a complex disease.
We began our investigation with a discovery screen containing SNPs from 73 genes with putative functional relationships to IL7RA and subsequently genotyped 7,865 single nucleotide polymorphism (SNPs) in and around these genes. Two of the gene regions examined, IL7 and SOCS1, had significantly associated SNPs that further replicated in an independent case-control dataset with joint p-values reaching 8.29x10-5 and 3.48x10-7, respectively, exceeding the threshold for experiment-wide significance. Our results also implicated two additional novel gene regions that are likely to be associated with MS: PRKCE with p-values reaching 3.47x10-4 and BCL2 with p-values reaching 4.32x10-4. The TYK2 gene, which emerged in our analysis, also has recently been associated with MS in other studies.
The work presented in this dissertation confirmed two novel regions and implicated several others that need further examination as MS disease loci. Thus, using the pathway approach in conjunction with large datasets and dense genotyping, the etiology of MS is finally starting to be dissected. By building on the knowledge of these gene effects, these studies will hopefully result in further understanding of the pathogenesis of MS.
Advisors/Committee Members: Subramanian Sriram (committee member), Dana Crawford (committee member), Michael Rock (committee member), Jonathan Haines (committee member), Marylyn Ritchie (Committee Chair).
Subjects/Keywords: autoimmune; susceptibility
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APA (6th Edition):
Zuvich, R. L. (2009). Pathway Approach to Decoding Multiple Sclerosis. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/15066
Chicago Manual of Style (16th Edition):
Zuvich, Rebecca Lynn. “Pathway Approach to Decoding Multiple Sclerosis.” 2009. Doctoral Dissertation, Vanderbilt University. Accessed April 17, 2021.
http://hdl.handle.net/1803/15066.
MLA Handbook (7th Edition):
Zuvich, Rebecca Lynn. “Pathway Approach to Decoding Multiple Sclerosis.” 2009. Web. 17 Apr 2021.
Vancouver:
Zuvich RL. Pathway Approach to Decoding Multiple Sclerosis. [Internet] [Doctoral dissertation]. Vanderbilt University; 2009. [cited 2021 Apr 17].
Available from: http://hdl.handle.net/1803/15066.
Council of Science Editors:
Zuvich RL. Pathway Approach to Decoding Multiple Sclerosis. [Doctoral Dissertation]. Vanderbilt University; 2009. Available from: http://hdl.handle.net/1803/15066
. 
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