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Shared Genetic Architecture of Red Blood Cell Traits in Us

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Shared Genetic Architecture of Red Blood Cell Traits in Us SHARED GENETIC ARCHITECTURE OF RED BLOOD CELL TRAITS IN U.S. POPULATIONS Chani Jo Hodonsky A dissertation submitted to the faculty at the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Epidemiology in the Gillings School of Global Public Health. Chapel Hill 2019 Approved by: Christy Avery Mariaelisa Graff Kari North Alex Reiner Ran Tao i 228 ©2019 Chani Jo Hodonsky ALL RIGHTS RESERVED ii ABSTRACT Chani Jo Hodonsky: Shared Genetic Architecture of Red Blood Cell Traits in U.S. Populations (Under the direction of Christy L. Avery) Red blood cells are the most numerous cell in the body, and clinical measures used to describe them (RBC traits) are highly polygenic. Hundreds of loci have been identified using traditional genome-wide association study methods. However, the majority of association studies have been performed in European- or East Asian-ancestry populations, and heritability estimates suggest that additional associations remain to be identified. Rare variants, which GWAS are typically underpowered to detect, have been considered as potential contributors to this missing heritability. Of note, European-ancestry populations have both the lowest genetic diversity and the fewest rare variants compared to other ancestry groups. Both the identification of previously unreported loci and the characterization of known loci for complex quantitative traits benefit from inclusive study populations and recently developed association study methods. The objective of this study was to evaluate genetic associations with seven RBC traits in an ancestrally diverse study population by applying two different methods—a combined-phenotype approach to evaluating common variants that may affect multiple RBC traits, and a gene-based approach that improves power to detect groups of rare variants acting on a single genetic transcript. We utilized data from a large, multi-ethnic study population from across the United States, including genotypes and data from seven RBC traits: hematocrit, hemoglobin concentration, mean corpuscular hemoglobin, mean corpuscular iii hemoglobin concentration, mean corpuscular volume, red blood cell count, and red cell distribution width. Our findings confirm the high polygenicity of RBC traits and the applicability of previously reported RBC trait loci to populations of all ancestries. We identified four previously unreported genes associated with one or more RBC traits. Additionally, using a combined- phenotype method we identified twenty independent association signals within seven loci, several of which had lead variants only present in African- or American-ancestry populations. Our work shows the importance of performing association studies in populations of all ancestries, while also calling for increased representation of genetic variation from diverse populations in publicly available resources such as eQTL databases. Continued efforts into the bioinformatic characterization of RBC trait loci will pave the way for molecular work that improves our understanding of RBC physiology and may lead to pharmaceutical innovations for genetically or environmentally induced RBC disorders. iv I dedicate this work to my parents, Pamela and Joseph Hodonsky; my brother, Eric Hodonsky; and Dr. Paul and Phyllis Schroeder. I am forever grateful for your love and support throughout this journey. v ACKNOWLEDGMENTS I would like to thank my dissertation committee (Marielisa Graff, Kari North, Alex Reiner, and Ran Tao) and chair (Christy Avery) for making this work possible. Each member of my committee offered a breadth and depth of knowledge that inspire me to continue improving every day as I strike out on my own research path. The work represented by this document may have been performed by me, but would never have been possible without the guidance and encouragement of my family and friends. I begin by thanking my parents, Pam and Joe Hodonsky, who supported me on the winding road of self discovery that ultimately led to the UNC epidemiology program. They were there every step of the way, and that unconditional love sustained me. My brother, Eric Hodonsky, provided a consistent source of love and positive words, checking in from the west coast to make sure I was surviving the travails of coursework and research. I also thank and honor Dr. Paul and Phyllis Schroeder, without whom I could never have become the person I am today. I can only hope to aspire to their boundless love and generosity. The life of a PhD student can be a rollercoaster, and over the last five years a large number of people have ridden that rollercoaster with me. I would like to thank my friends and colleagues in the Gillings School of Public Health, who were there to help me grow as a student and researcher: Breakfast Club (Antoine Baldassari, Joseph Engeda, and Rahul Gondalia), Elizabeth Kamai, Paula Strassle, Nikki Niehoff, Kristin Voltzke Moore, Rebecca Stebbins, Sydney Thai, Adrien Wilkie, Mackenzie Herzog, Kamika Reynolds, Liz Kelly, Magdalene vi Assimon, Anne Justice, Kris Young, Laura Raffield, and Heather Highland. I would also like to thank my “non-epi” friends who loved me (and occasionally fed me) despite the demands of graduate school: Suzanne and Angela Derby-Wright, Hope Tyson, Zinaida Mahmutefendic and Andrew Hunt, Dylan Williams, Amber Sniff and Jim Heffernan, Dan Mott and Jennifer Robinson, Lily and Michael Whitton, Kim and Lars Soltmann, Sam Boyarsky, Rim Vilgalys, Boris Kurktchiev and Kelli Avalos, Will Roper and Sam Ross, Brent Eason, and Cheralyn Schmidt. I have also had friends from all parts of my life supporting me from afar throughout this process, whom I love and am so glad to have in my life. A special thank you to Eric Witham, Eric Dennis, Johanna and Wes Craig, Gabrielle and Clare Singleton, Andrew Inman, Michael Garrison, and Ravin Pan for watching me grow up and loving me anyway. Finally, I have been extremely fortunate to learn from mentors across every aspect of my life. I would specifically like to thank Janet Hegman Shier, John Rubadeau, Tony Antonellis, Ming-Sing Si, Steve Leibovic, and Arash Babaoff for showing me the best of humanity. I am honored to have been a member of the PAGE study for the entirety of my graduate work, and I look forward to continuing this collaboration. PAGE has provided an environment of support, generous authorship opportunities, and a shining example of what collaboration in academic science should be. While all of my PAGE collaborators made me feel welcome over the past five years, I would specifically like to thank Drs. Stephanie Bien, Genevieve Wojcik, Christopher Gignoux, Eimear Kenny, Lucia Hindorff, and Charles Kooperberg. I would also like to acknowledge the contributions of the nearly 100,000 study participants who selflessly gave their time and resources to move forward the fields of cardiovascular and genetic epidemiology. Lastly, I am grateful for the opportunity to focus on my work as a trainee of the NIH/NHLBI T32 Cardiovascular Genetic Epidemiology Training Grant (T32 HL129982). vii TABLE OF CONTENTS LIST OF TABLES ....................................................................................................................... xiii LIST OF FIGURES .................................................................................................................... xvii LIST OF ABBREVIATIONS .................................................................................................... xviii LIST OF GENE NAMES ........................................................................................................... xxii OVERVIEW AND RATIONALE .......................................................................... 1 SPECIFIC AIMS .................................................................................................... 4 2.1. Aim 1: Leverage evidence of pleiotropy to identify and characterize RBC trait loci. 4 2.2. Aim 2: Identify rare variants associated with RBC traits via gene-based analysis. ... 4 BACKGROUND AND SIGNIFICANCE............................................................. 6 3.1. Historical background ................................................................................................. 6 3.2. Red blood cell biology ................................................................................................ 7 3.2.1. Three waves of hematopoiesis ................................................................................ 8 3.2.2. Hemoglobin: the primary actor in RBC oxygen transportation and delivery ......... 9 3.2.3. Stages of Erythropoiesis and RBC Degradation ................................................... 10 3.2.4. Iron homeostasis in erythropoiesis........................................................................ 12 3.3. Red blood cell trait definitions and measurement..................................................... 13 3.3.1. HCT....................................................................................................................... 14 3.3.2. HGB ...................................................................................................................... 15 3.3.3. RBCC .................................................................................................................... 15 3.3.4. MCH ..................................................................................................................... 15 3.3.5. MCHC ..................................................................................................................
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