Towards personalized medicine in understudied populations : coagulation and anti-coagulation in African Americans
- Personalized genomic medicine uses a patient's genetic information to assess disease risk or to make decisions about drug dosing. However, genetic risk variants in one population do not always represent risk in another population. Research across a diverse set of populations identify important population-specific risk variants, and reveal new biology by associating new pathways to a phenotype. In this thesis, I undertook multiple studies that addressed personalized genomic medicine in the context of diverse populations. First, I developed a tool for assessing ClinVar designated pathogenic variants in genetic data. I studied the distribution of variation across different populations and found differences between populations in the number of Clinvar designated pathogenic variants. Most studies look at genetic variants in isolation -- that is, each variant is tested for an association with a phenotype. However, these methods make it difficult to detect signal from rare variants and variants of modest effect. I created a method of aggregating variants across a biologically relevant pathway to detect signal missed in single loci analysis. With this method, I showed that the aggregate variation across the warfarin metabolic pathway explains some of the missing heritability in that phenotype. Finally, I focus on the genetics of diagnosing and treating clotting disorders in African Americans, a population with great phenotypic variability and understudied genetic risk. In this domain, I (1) created a method of aggregating variants across a biologically relevant pathway to detect signal missed in single loci analysis, which showed that the aggregate variation across the warfarin metabolic pathway explains some of the missing heritability in that phenotype; (2) identified a missense mutation (Val510Met) in the anti-coagulant Protein S which is associated with abnormal clotting in the African American population using a family study and a case-control analysis of 205 individuals; (3) using an extreme phenotype design and exome sequencing, I identified a population-specific regulatory variant in folylpolyglutamate synthase (FPGS), which is associated with lower warfarin dose in the African American population. In order to broadly understand the genetic risk factors affecting disease and drug phenotypes, we need studies in diverse populations. Here, I identified new, population specific variation associated with two such phenotypes -- coagulation and anticoagulation -- in an African American population.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|Daneshjou, Roxana Rose
|Stanford University, Department of Genetics.
|Snyder, Michael, Ph. D
|Snyder, Michael, Ph. D
|Statement of responsibility
|Roxana Rose Daneshjou.
|Submitted to the Department of Genetics.
|Thesis (Ph.D.)--Stanford University, 2016.
- © 2016 by Roxana Daneshjou
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...